Immunomodulation by targeted anticancer agents
Open accessAbstract
At odds with conventional chemotherapeutics, targeted anticancer agents are designed to inhibit precise molecular alterations that support oncogenesis or tumor progression. Despite such an elevated degree of molecular specificity, many clinically employed and experimental targeted anticancer agents also mediate immunostimulatory or immunosuppressive effects that (at least in some settings) influence therapeutic efficacy. Here, we discuss the main immunomodulatory effects of targeted anticancer agents and explore potential avenues to harness them in support of superior clinical efficacy.
AI snapshot
Written from the paper’s full text.
TL;DR
This review argues that targeted anticancer agents, despite being designed for molecular specificity, frequently modulate immune responses in ways that can either support or undermine therapeutic efficacy. It catalogs these immunostimulatory and immunosuppressive effects across major drug classes and proposes combining targeted agents with immune checkpoint inhibitors and other immunotherapies.
Key findings
Many targeted agents mediate net immunostimulation through improved antigen presentation, pro-inflammatory cytokine release, immunogenic cell death, NK-cell activation, or depletion of regulatory T cells and myeloid-derived suppressor cells; examples span CDK4/6 inhibitors, BRAF/MEK inhibitors, PARP inhibitors, EGFR/HER2-targeting antibodies, and VEGFA/TGFβ inhibitors. Conversely, the same classes can also drive immunosuppression, often via PD-L1 upregulation, T-cell exhaustion, M2-like macrophage polarization, or MDSC expansion, which provides a rationale for combining them with ICIs. The review notes that ICIs used alone produce durable responses in only about 15%–30% of patients depending on the oncological setting, while seven ICIs are approved by the FDA or equivalent agencies. It also suggests that clinical development may have positively selected targeted agents with net immunostimulatory activity, and that future development should incorporate immune-cell/cancer-cell co-culture screens, immunocompetent mouse models, and immunomonitoring starting in phase I trials.
Methods
Narrative review; no primary experiments, systematic search strategy, or meta-analysis are described. The authors synthesize preclinical and clinical literature and provide five tables mapping targets, agents, FDA approval status, cancer-cell-dependent versus immune-cell-dependent effects, notes, and references. The synthesis is organized thematically by drug class: CDK inhibitors, KRAS/PI3K signaling inhibitors, DDR- and apoptosis-targeting agents, HER2/EGFR/VEGFA/TGFβ inhibitors, and other targeted agents.
Limitations
Stated in the paper: the authors apologize for omitting high-profile articles because of space constraints, and they note that the biology of immunomodulation by targeted agents is still emerging, with unresolved questions about drug specificity, mechanisms, divergent effects across settings, and optimal combinatorial schedules. Evident from the text: this is a narrative review without a systematic search or quantitative synthesis; many cited findings are preclinical or context-dependent; the tables mix approved and experimental agents without formal risk-of-bias assessment; and the proposed combinatorial strategies are not validated by primary data in the review itself.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 378 cited sources checked · 0 supported · 0 flagged
- Premisecitation§ INTRODUCTION · p. 1
Imatinib's clinical activity has a link to immune functions.
“an unexpected link between the clinical activity of imatinib and immune functions emerged (Zitvogel et al., 2016)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zitvogel et al., 2016 source
Not checked in the free run.
- Premisecitation§ Box 1. ICD in cancer therapy · p. 2
Targeted anticancer agents can induce an immunogenic form of cancer cell death that initiates the cancer-immunity cycle.
“targeted anticancer agents can trigger a highly immunogenic variant of cancer cell death to jumpstart the so-called cancer-immunity cycle (Galluzzi et al., 2017b)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Galluzzi et al., 2017b
Not checked in the free run.
- Premisecitation§ Box 1. ICD in cancer therapy · p. 2
Most targeted anticancer drugs currently approved for patient use produce at least some therapeutically relevant immune stimulation.
“most targeted anticancer agents currently approved for use in patients mediate (at least some degree of) therapeutically relevant immunostimulation”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Galluzzi et al., 2015 source
Not checked in the free run.
- Interpretationnone given§ SUMMARY · p. 1
A broad set of targeted anticancer drugs, both approved and experimental, produce immune-stimulating or immune-suppressing effects that can affect how well treatment works in certain contexts.
“Despite such an elevated degree of molecular specificity, many clinically employed and experimental targeted anticancer agents also mediate immunostimulatory or immunosuppressive effects that (at least in some settings) influence therapeutic efficacy.”
Quote in the paperSubstantial claim - Interpretationnone given§ INTRODUCTION · p. 1
Imatinib and nearly all other targeted anticancer agents developed over the past three decades exert immune-stimulating or immune-suppressing effects that can affect treatment efficacy.
“A large amount of preclinical and clinical data indicates that imatinib and virtually all other targeted anticancer agents developed over the past three decades indeed exert”
Quote in the paperSubstantial claim
- Premisereasoning§ Box 1. ICD in cancer therapy · p. 2
Immune modulation by targeted anticancer therapy may depend on the death of malignant or immune cells.
“immunomodulation by targeted anticancer therapy can (but does not necessarily) hinge on the demise of malignant or immune cells.”
Quote in the paperNot a substantial claim - Interpretationcitation§ Box 1. ICD in cancer therapy · p. 2
The clinical development process appears to have favored agents that enhance anticancer immunity over those that suppress it.
“suggesting that clinical development has positively selected for molecules that support, rather than restrain, anticancer immunity (Galluzzi et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Galluzzi et al., 2015 source
Not checked in the free run.
- Premisecitation§ Box 1. ICD in cancer therapy · p. 2
Targeted anticancer agents can selectively eliminate immunosuppressive cells such as regulatory T cells.
“or selectively promote the depletion of immunosuppressive cells that would otherwise favor disease progression, such as regulatory T (TREG) cells (Galluzzi et al., 2018)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Galluzzi et al., 2018 source
Not checked in the free run.
- Interpretationreasoning§ ll · p. 6
In some cases, CDK inhibitor immune stimulation is accompanied by direct or compensatory immunosuppression, generally manifesting as PD-L1 upregulation.
“In some cases, such immunostimulatory activity is accompanied by at least some degree of direct or compensatory immunosuppression that generally manifests with PD-L1 upregulation.”
Quote in the paperNot a substantial claim - Interpretationcitation§ Box 1. ICD in cancer therapy · p. 2
Correlative evidence supports an association between anticancer immunity downstream of ICD and better disease outcomes across several oncological settings.
“abundant correlative data support the contention that anticancer immunity downstream of ICD is associated with improved disease outcome in a variety of oncological settings.”
Quote in the paperSubstantial claim - Premisecitation§ Review Cell · p. 6
The immune-stimulating effect of CDK4/CDK6 inhibitors is partly counteracted by their upregulation of PD-L1 through transcriptional and post-translational mechanisms.
“At least in part, the immunostimulatory activity of CDK4/CDK6 inhibitors is offset by their ability to upregulate the immunosuppressive molecule CD274 (best known as programmed deathligand 1 [PD-L1]) via transcriptional and post-translational mechanisms (Jin et al., 2019b; Zhang et al., 2018a).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Jin et al., 2019b
Not checked in the free run.
- cites Zhang et al., 2018a
Not checked in the free run.
- Premisecitation§ Box 1. ICD in cancer therapy · p. 2
Surface exposure of calreticulin by malignant cells as an adjuvant-like signal correlates with better outcomes in acute myeloid leukemia and ovarian carcinoma.
“the ability of malignant cells to proficiently expose the endoplasmic reticulum (ER) protein calreticulin (CALR) on their surface as an adjuvantlike signal has been associated with superior disease outcome in patients with acute myeloid leukemia (Truxova et al., 2020) and ovarian carcinoma (Kasikova et al., 2019).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ Cell · p. 3
CDK4/CDK6 inhibitors activate effector T cells through NFAT signaling and IL2 secretion.
“activation of effector T (TEFF) cells upon nuclear factor of activated T cells 1 (NFATC1, best known as NFAT) signaling and interleukin-2 (IL2) secretion (Deng et al., 2018)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Deng et al., 2018 source
Not checked in the free run.
- Interpretationcitation§ ll · p. 6
CDK-targeting agents, including several FDA-approved drugs, produce robust immune stimulation that supports treatment efficacy.
“In summary, CDK-targeting agents, including several FDAapproved molecules, have been shown to mediate robust immunostimulatory effects that support treatment efficacy (Table 1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Table 1
Not checked in the free run.
- Premisecitation§ ll · p. 6
The multi-CDK inhibitor dinaciclib blocks IFNG-driven upregulation of PD-L1 and IDO1 in mouse pancreatic adenocarcinoma models, preventing adaptive immune resistance.
“the multi-CDK inhibitor dinaciclib blocks the interferon gamma (IFNG)-driven upregulation of PD-L1 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in mouse models of pancreatic adenocarcinomas, ultimately preventing adaptive immune resistance (Huang et al., 2020b).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Huang et al., 2020b
Not checked in the free run.
- Premisecitation§ Cell · p. 3
Several CDK4/CDK6 inhibitors stimulate immunity by directly interacting with immune cells.
“various CDK4/CDK6 inhibitors have been shown to mediate a variety of immunostimulatory effects by directly interacting with immune cells (Petroni et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Petroni et al., 2020 source
Not checked in the free run.
- Interpretationcitation§ Review Cell · p. 6
CDKs other than CDK4 and CDK6 can be targeted to achieve therapeutically relevant immune stimulation.
“CDKs other than CDK4 and CDK6 can also be actioned to achieve therapeutically relevant immunostimulation.”
Quote in the paperSubstantial claim - Premisecitation§ Review Cell · p. 6
Combining palbociclib with an anti-HER2 monoclonal antibody produces similar results in a transgenic HER2+ breast cancer model.
“Similar results have been obtained by combining palbociclib with a monoclonal antibody (mAb) specific for erb-b2 receptor tyrosine kinase 2 (ERBB2, best known as HER2) in a transgenic model of HER2 + breast cancer (MMTV-neu202 Mul mice) (Wang et al., 2019a).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2019a
Not checked in the free run.
- Premisecitation§ Box 1. ICD in cancer therapy · p. 2
Loss-of-function polymorphisms in genes for immune receptors that recognize ICD-associated adjuvant-like molecules correlate with poor outcomes in breast cancer patients given anthracycline-based chemotherapy.
“loss-of-function polymorphisms in various genes encoding immune receptors involved in the recognition of ICD-associated adjuvant-like molecules have been linked with poor disease outcome in cohorts of breast cancer patients receiving ICD-inducing anthracycline-based chemotherapy (Fucikova et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Fucikova et al., 2015 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 6
PI3Kα and BCL2 blockers enhance the capacity of CDK4/CDK6 inhibitors to promote antigen presentation and PD-L1 expression in breast cancer models.
“both phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, best known as PI3K a ) and BCL2 apoptosis regulator (BCL2) blockers boost the ability of CDK4/CDK6 inhibitors to promote antigen presentation (as well as PD-L1 expression) in models of breast cancer”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ CYCLIN-DEPENDENT KINASE INHIBITORS · p. 2
In several preclinical tumor models, abemaciclib-mediated CDK4/CDK6 inhibition stimulates immunity by increasing MHC class I exposure on cancer cells.
“In various preclinical tumor models, CDK4/CDK6 inhibition with abemaciclib mediates immunostimulatory effects by promoting the exposure of MHC class I molecules on the cancer cell surface (Goel et al., 2017; Schaer et al., 2018).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ Cell · p. 3
The MHC class I peptidome of human melanoma cells treated with palbociclib is enriched for tumor-associated antigens and peptides from E2F target proteins involved in cell cycle blockage.
“the MHC class I peptidome of human melanoma cells exposed to the CDK4/CDK6 inhibitor palbociclib is enriched for tumor-associated antigens (TAAs) and peptides from E2F target proteins that are directly implicated in cell cycle blockage (Stopfer et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Stopfer et al., 2020 source
Not checked in the free run.
- Interpretationreasoning§ ll · p. 6
ICIs targeting the PD-1/PD-L1 axis are promising candidates to improve the clinical activity of CDK inhibitors.
“Thus, ICIs targeting the PD-1/PD-L1 axis stand out as promising candidates to improve the clinical activity of CDK inhibitors.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Box 1. ICD in cancer therapy · p. 2
ICD is an important therapeutic goal, particularly in combinations that pair ICD-driven anticancer immunity with immune checkpoint inhibitors or other immunotherapy.
“Thus, ICD stands out as a prominent goal for cancer therapy, especially in the context of combinatorial treatment regimens harnessing ICD-driven anticancer immune responses with immune checkpoint inhibitors (ICIs, see Box 2) or other forms of”
Quote in the paperSubstantial claim - Premisecitation§ Box 1. ICD in cancer therapy · p. 2
A T-cell clone specific for a radiation-upregulated tumor neoantigen expanded in the blood of a non-small cell lung cancer patient who had a complete response to radiation plus ipilimumab.
“the expansion of a T-cell clone specific for a tumor neoantigen upregulated by radiation has been documented in the blood of a patient with non-small cell lung carcinoma experiencing a complete response to RTplus the cytotoxic T lymphocyte-associated protein 4 (CTLA4) blocker ipilimumab (Formenti et al., 2018b).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Formenti et al., 2018b
Not checked in the free run.
- Premisecitation§ Cell · p. 3
CDK4/CDK6 inhibitors stimulate immunity by promoting secretion of pro-inflammatory cytokines such as type III interferon and CCL5.
“CDK4/CDK6 inhibitors mediate immunostimulatory effects by favoring the secretion of pro-inflammatory cytokines such as type III interferon (Goel et al., 2017) and CC-chemokine ligand 5 (CCL5) (Vilgelm et al., 2016).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ Review Cell · p. 6
In preclinical KRAS-driven lung and pancreatic adenocarcinoma models, trametinib and palbociclib synergize to induce a SASP-dependent vascular response that allows immune effector cells to infiltrate tumors.
“trametinib synergizes with palbociclib at inducing a SASP-dependent vascular response that enables tumor infiltration by immune effector cells”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ KRAS AND PI3K SIGNALING INHIBITORS · p. 6
BRAF and MEK inhibitors upregulate tumor-associated antigens.
“upregulation of TAAs (Boni et al., 2010; Frederick et al., 2013)”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ KRAS AND PI3K SIGNALING INHIBITORS · p. 6
BRAF and MEK inhibitors improve antigen presentation on MHC class I molecules.
“improved antigen presentation on MHC class I molecules (Dushyanthen et al., 2017; Kang et al., 2019; Liu et al., 2015)”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ KRAS AND PI3K SIGNALING INHIBITORS · p. 6
BRAF and MEK inhibitors induce ICD.
“induction of ICD (Box 1) (Erkes et al., 2020; Wang et al., 2020a)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Erkes et al., 2020 source
Not checked in the free run.
- cites Wang et al., 2020a
Not checked in the free run.
- Premisecitation§ KRAS AND PI3K SIGNALING INHIBITORS · p. 6
BRAF and MEK inhibitors promote secretion of TH1 cytokines such as CXCL9 and CXCL10.
“secretion of TH1 cytokines such as CXCL9 and CXCL10 (Kang et al., 2019)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kang et al., 2019 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 11
Pulmonary carcinogenesis driven by Kras activation and Tp53 loss is associated with an altered microbiota linked to disturbed cytokine signaling.
“pulmonary carcinogenesis driven by Kras activation and Tp53 loss has been associated with an altered microbiota linked to deranged cytokine signaling (Jin et al., 2019a)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jin et al., 2019a
Not checked in the free run.
- Interpretationcitation§ ll · p. 11
The detrimental effect of MEK inhibition can be at least partly avoided or reversed by agents other than PD-1/PD-L1 blockers, including CTLA4 or TIM-3 blockers, especially with cyclic MEK inhibition.
“such a potentially detrimental effect can be avoided or reversed (at least in part) with a variety of agents other than PD-1/PD-L1 blockers, including (but not limited to) (1) cytotoxic T lymphocyte-associated protein 4 (CTLA4) or hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM-3) blockers, especially in the context of cyclic MEK inhibition (Choi et al., 2019; Liu et al., 2017b)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Choi et al., 2019 source
Not checked in the free run.
- cites Liu et al., 2017b
Not checked in the free run.
- Premisecitation§ ll · p. 11
Combined BRAF and MEK inhibition raises PD-L1, PD-L2, and PD-1 on the surface of malignant cells in melanoma models.
“the ability of BRAF and MEK co-inhibition to upregulate not only PD-L1 and PDCD1 ligand 2 (PDCD1LG2, best known as PD-L2) but also PD-1, on the surface of malignant cells (Sanlorenzo et al., 2018)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sanlorenzo et al., 2018 source
Not checked in the free run.
- Premisecitation§ KRAS AND PI3K SIGNALING INHIBITORS · p. 6
BRAF and MEK inhibitors, including vemurafenib, dabrafenib, and trametinib, produce cancer-cell-dependent immunostimulatory effects.
“both BRAF and MEK inhibitors (including the FDA-approved agents vemurafenib, dabrafenib, and trametinib) mediate various cancer-cell-dependent immunostimulatory effects”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ ll · p. 11
The BRAF inhibitor PLX4720 has immunostimulatory effects on NK cells, increasing CD69 expression and IFNG secretion when IL2 is present.
“the BRAF inhibitor PLX4720 reportedly mediates immunostimulatory effects on NK cells by favoring CD69 expression and boosting IFNG secretion in the context of IL2 stimulation (Ferrari de Andrade et al., 2014)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ferrari de Andrade et al., 2014 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 11
Hyperactive PI3K signaling, whether caused by PI3KCA mutations or PTEN deletions, promotes immunosuppression in developing tumors.
“hyperactive PI3K signaling, be it a consequence of PI3KCA mutations or PTEN deletions, also promotes the establishment of immunosuppression by developing tumors (Spranger and Gajewski, 2018)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Spranger and Gajewski, 2018
Not checked in the free run.
- Premisecitation§ KRAS AND PI3K SIGNALING INHIBITORS · p. 6
Activating KRAS and BRAF mutations in malignant cells support an immunosuppressive microenvironment through multiple mechanisms.
“Activating KRAS and BRAF mutations in malignant cells support the establishment of an immunosuppressive microenvironment by multiple mechanisms (Spranger and Gajewski, 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Spranger and Gajewski, 2018
Not checked in the free run.
- Premisecitation§ ll · p. 11
AMG 510 induces immunogenic cell death.
“the ability of AMG 510 to induce ICD (Canon et al., 2019)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Canon et al., 2019 source
Not checked in the free run.
- Premisecitation§ ll · p. 11
Trametinib increases PD-L1 expression in mouse breast cancer cells both in vitro and in vivo.
“trametinib promotes PD-L1 upregulation in mouse breast cancer cells, in vitro and in vivo (Loi et al., 2016)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Loi et al., 2016 source
Not checked in the free run.
- Interpretationcitation§ Review Cell · p. 11
CDK4/CDK6 inhibitors can avoid or reverse the detrimental effect of MEK inhibition.
“(3) CDK4/CDK6 inhibitors (Teh et al., 2020)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Teh et al., 2020 source
Not checked in the free run.
- Premisecitation§ ll · p. 11
When tumors progress on KRAS, BRAF, or MEK inhibitors, loss of antigen presentation, effector T cell exhaustion, and infiltration by immunosuppressive cells are commonly seen in both preclinical and clinical settings.
“loss of antigen presentation, TEFF cell exhaustion, and tumor infiltration by immunosuppressive cells have been commonly observed when tumors progress on KRAS, BRAF, or MEK inhibitors, in both preclinical (Dushyanthen et al., 2017; Liu et al., 2017b) and clinical settings (Frederick et al., 2013; Hugo et al., 2015)”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ ll · p. 11
MEK inhibitors directly restrict the expansion of CD11b+CD14+ bone marrow-derived MDSCs.
“the ability of MEK inhibitors to directly limit the expansion of CD11b + CD14 + bone marrow-derived MDSCs (Allegrezza et al., 2016a)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Allegrezza et al., 2016a
Not checked in the free run.
- Interpretationcitation§ ll · p. 11
Inhibitors of KRAS or its main downstream transducers generally produce immunostimulatory effects that contribute to their efficacy.
“Thus, various inhibitors of KRAS or its main transducers mediate immunostimulatory effects that contribute to efficacy.”
Quote in the paperSubstantial claim - Premisecitation§ Review Cell · p. 11
PTEN competence is associated with a higher incidence of PD-L1+ cases in melanoma patients.
“PTEN competence is associated with an increased incidence of PD-L1 cases in melanoma patients (Peng et al., 2016)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Peng et al., 2016 source
Not checked in the free run.
- Interpretationcitation§ Review Cell · p. 11
The main therapeutic effect of systemic PI3Kδ inhibition may come from depletion of TREG cells.
“suggesting that the main therapeutic component of systemic PI3K d inhibition may originate from TREG cell depletion (Lim et al., 2018)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lim et al., 2018 source
Not checked in the free run.
- Premisecitation§ ll · p. 12
PARP inhibitors are linked to PD-L1 increases in diverse cancer cells irrespective of BRCA1/2 status, probably through type I IFN or IFNG signaling.
“Importantly, the administration of PARP inhibitors has been associated with PD-L1 upregulation in various cancer cells regardless of BRCA1/2 status, presumably as a consequence of type I IFN or IFNG signaling (Chabanon et al., 2019; Jiao et al., 2017; Sen et al., 2019; Shen et al., 2019).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ Review Cell · p. 11
Dual PI3Kδ/PI3Kγ inhibition with duvelisib reduces PD-L1 expression by lymphoma cells.
“dual PI3K d /PI3K g inhibition with duvelisib limits PD-L1 expression by lymphoma cells (Harrington et al., 2019)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Harrington et al., 2019 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 12
MTOR inhibitors strongly activate autophagy.
“these agents potently activate autophagy (Galluzzi et al., 2017a)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Galluzzi et al., 2017a
Not checked in the free run.
- Premisecitation§ DDR- AND APOPTOSIS-TARGETING AGENTS · p. 12
Malignant cells with these defects can be highly dependent on DNA damage repair mechanisms or on robust antiapoptotic signaling.
“malignant cells bearing these defects exhibit an exquisite dependency on cDNA damage repair (DDR) mechanisms or robust antiapoptotic signaling, which has been harnessed for the development of targeted anticancer agents based on the principle of synthetic lethality (Huang et al., 2020a)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Huang et al., 2020a
Not checked in the free run.
- Interpretationcitation§ Review Cell · p. 12
MTOR inhibitors are not expected to produce the same antigen presentation activity.
“MTOR inhibitors are not expected to mediate a similar activity, largely reflecting the notions that these agents potently activate autophagy (Galluzzi et al., 2017a) and that autophagy limits MHC class I levels on the surface of malignant cells (Yamamoto et al., 2020)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Galluzzi et al., 2017a
Not checked in the free run.
- cites Yamamoto et al., 2020 source
Not checked in the free run.
- Premisecitation§ ll · p. 12
Genomic stress and DDR defects promote cytosolic accumulation of single-stranded DNA, which supports oncosuppressive processes including a cancer-cell-dependent immunostimulatory response driven by CGAS and STING.
“Both genomic stress and DDR defects favor the cytosolic accumulation of single-stranded DNA (ssDNA) in support of various oncosuppressive processes, including a cancer-celldependent immunostimulatory response driven by cyclic GMPAMP synthase (CGAS) and stimulator of interferon response cGAMP interactor 1 (STING1; best known as STING) (Vanpouille-Box et al., 2018)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vanpouille-Box et al., 2018 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 11
Mice with an inactivating mutation in Pik3cd show superior resistance to chronic lymphocytic leukemia when TREG cell expansion is impaired.
“mice bearing an inactivating mutation in Pik3cd exhibit superior resistance to chronic lymphocytic leukemia (CLL) in the context of impaired TREG cell expansion (Dong et al., 2019; Hanna et al., 2019)”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ DDR- AND APOPTOSIS-TARGETING AGENTS · p. 12
Several PARP1 inhibitors are approved for cancers with DDR defects, such as breast and ovarian tumors with BRCA1 or BRCA2 mutations.
“multiple poly(ADP)-ribose polymerase 1 (PARP1) inhibitors are licensed for the treatment of cancers bearing DDR defects, such as breast and ovarian tumors bearing BRCA1 or BRCA2 mutations (Pilie ´ et al., 2019)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Pilie ´ et al., 2019 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 12
Autophagy strongly inhibits type I IFN secretion by breast cancer cells responding to radiation.
“autophagy is a potent inhibitor of type I IFN secretion by breast cancer cells responding to radiation (Rodriguez-Ruiz et al., 2019; Yamazaki et al., 2020)”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ ll · p. 12
The ability of PARP inhibitors to drive type I IFN synthesis is linked to PARP1 trapping on DNA and cannot be reproduced by PARP1 degradation.
“the ability of PARPinhibitors to drive type I IFN synthesis appears to be linked to PARP1 trapping on DNA, as it cannot be recapitulated by PARP1 degradation (Kim et al., 2020)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kim et al., 2020 source
Not checked in the free run.
- Interpretationreasoning§ Review Cell · p. 12
In certain settings, T-cell exhaustion becomes a resistance mechanism that can be overcome by various immunotherapeutics beyond immune checkpoint inhibitors.
“in specific settings T-cell exhaustion emerges as a mechanism of resistance that can be overcome by a variety of immunotherapeutics beyond ICIs”
Quote in the paperSubstantial claim - Premisecitation§ Review Cell · p. 12
PI3K and AKT1 inhibitors boost IFNG-driven class I and class II antigen presentation as a mechanism of cancer-cell-dependent immunostimulation.
“PI3K and AKT1 inhibitors have also been shown to boost IFNG-driven class I and class II antigen presentation as a mechanism of cancer-cell-dependent immunostimulation (Chandrasekaran et al., 2019; Marijt et al., 2019; Sivaram et al., 2019)”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ Review Cell · p. 11
Duvelisib correlates with repolarization of the TAM compartment toward immunostimulation.
“correlating with a repolarization of the TAM compartment toward immunostimulation (Horwitz et al., 2018)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Horwitz et al., 2018 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 11
PTEN silencing in melanoma cells does not affect PD-L1 levels.
“PTEN silencing in melanoma cells fails to affect PD-L1 levels (Peng et al., 2016)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Peng et al., 2016 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 11
The pan-class I PI3K inhibitor buparlisib synergizes with PD-1 blockers in controlling mouse breast cancers in immunocompetent hosts.
“the pan-class I PI3K inhibitor buparlisib synergizes with PD-1 blockers in the control of mouse breast cancers established in immunocompetent hosts (Sai et al., 2017)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sai et al., 2017 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 12
Autophagy reduces MHC class I levels on the surface of malignant cells.
“autophagy limits MHC class I levels on the surface of malignant cells (Yamamoto et al., 2020)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yamamoto et al., 2020 source
Not checked in the free run.
- Interpretationreasoning§ Review Cell · p. 12
Inhibitors of KRAS and PI3K signaling generally produce strong and therapeutically relevant immunostimulation.
“inhibitors of KRAS and PI3K signaling generally exert robust and therapeutically relevant immunostimulation (Table 2)”
Quote in the paperSubstantial claim - Premisecitation§ Review Cell · p. 12
Autophagy activation in cancer cells dying from chemotherapy is required for the cell death to be perceived as immunogenic.
“autophagy activation in cancer cells succumbing to chemotherapy is critical for cell death to be perceived as immunogenic (Box 1) (Michaud et al., 2011)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Michaud et al., 2011 source
Not checked in the free run.
- Premisecitation§ ll · p. 12
Various FDA-approved and experimental PARP inhibitors drive strong type I IFN secretion after increased cytosolic availability of ssDNA or micronuclei in many tumors, including BRCA1- and BRCA2-deficient neoplasms.
“various FDA-approved and experimental PARP inhibitors have been shown to drive robust type I IFN secretion downstream of increased cytosolic availability of ssDNA or micronuclei (DNAcontaining structures generally formed by faulty mitoses) in a variety of tumors, including (but not limited to) BRCA1- and BRCA2-deficient neoplasms (Chabanon et al., 2019; Ding et al., 2018; Pantelidou et al., 2019;”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationnone given§ ll · p. 12
All DDR-targeting agents have been shown to produce immunomodulatory effects of therapeutic relevance.
“all these DDR-targeting agents have been shown to mediate immunomodulatory effects of therapeutic relevance (Table 3)”
Quote in the paperNot a substantial claim - Premisecitation§ Review Cell · p. 11
Deletion of Pik3cg in the host enables superior CD8+ CTL functions.
“phosphatidylinositol4,5-bisphosphate 3-kinase catalytic subunit gamma ( Pik3cg ) deletion in the host enables superior CD8 + CTL functions”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sai et al., 2017 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 11
Dual PI3Kα/PI3Kδ blockage by copanlisib is linked to limited NFκB signaling and therefore inhibited secretion of immunomodulatory cytokines such as IL6 and IL10.
“dual PI3K a /PI3K d blockage by copanlisib has been linked to limited NFk B signaling and hence inhibited secretion of immunomodulatory cytokines like IL6 and IL10 (Paul et al., 2017)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Paul et al., 2017 source
Not checked in the free run.
- Premisecitation§ ll · p. 12
Pharmacological inhibition of PARP1 by veliparib or olaparib produces immunostimulatory effects by causing CGAS-independent upregulation of NKALs and death receptors on malignant cells, increasing their sensitivity to NK cell cytotoxicity.
“pharmacological inhibition of PARP1 by veliparib or olaparib reportedly mediates immunostimulatory effects by favoring the CGAS-independent upregulation of NKALs and death receptors on the surface of malignant cells, ultimately increasing their sensitivity to NKcell cytotoxicity (Fenerty et al., 2018; Paczulla et al., 2019)”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ Review Cell · p. 11
The PI3Kδ blocker idelalisib limits recruitment of immunosuppressive follicular helper T and TREG cells to the tumor microenvironment of follicular lymphoma.
“the PI3K d blocker idelasilib limits the recruitment of immunosuppressive follicular helper T (TFH) and TREG cells to the TME of follicular lymphoma (Serrat et al., 2020)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Serrat et al., 2020 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 12
Autophagy supports the development and function of several immune effector cells, including DCs, macrophages, CD4+ T cells, CD8+ T cells, and NK cells.
“autophagy supports the development and function of various immune effector cells, including DCs, macrophages, as well as CD4 + , CD8 + , and NK cells (Clarke and Simon, 2019)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Clarke and Simon, 2019 source
Not checked in the free run.
- Premisecitation§ ll · p. 12
Immune checkpoint inhibitors have been used successfully to increase the therapeutic activity of PARP inhibitors in preclinical tumor models.
“Indeed, various ICIs have been successfully harnessed to enhance the therapeutic activity of PARP inhibitors in preclinical tumor models (Ding et al., 2018; Jiao et al., 2017; Sen et al., 2019; Shen et al., 2019; Wang et al., 2019b).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ ll · p. 16
In vivo, ABT-737 is associated with increased tumor infiltration by MHC class II-expressing tumoricidal macrophages and CTLs.
“In vivo , this has been associated with increased tumor infiltration by MHC class II-expressing tumoricidal macrophages and CTLs (Giampazolias et al., 2017; Saito et al., 2019).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ ll · p. 16
ABT-737 administration is associated with TEFF depletion and TREG enrichment in tumor-free mice.
“Moreover, ABT-737 increases the sensitivity of MDSCs to FAS-driven apoptosis in vitro and suppresses MDSC accumulation in murine mammary carcinomas (Hu et al., 2013), even though its administration has been related to depletion of TEFF cells and enrichment of TREG cells in tumorfree mice (Gabriel et al., 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gabriel et al., 2016 source
Not checked in the free run.
- Premisecitation§ ll · p. 16
MDM2 inhibitors favor PD-L1 upregulation in vivo.
“Most likely reflecting such a robust immunostimulation, MDM2 inhibitors reportedly favor PD-L1 upregulation in vivo (Fang et al., 2019; Li et al., 2020a; Thiem et al., 2019), pointing to a potential value for combinatorial regimens involving ICIs.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ ll · p. 16
Alisertib promotes CD8+ T-cell tumor infiltration through a non-canonical pathway involving IL10 secretion.
“Consistent with this notion, the AURKA inhibitor alisertib appears to promote tumor infiltration of CD8 + T cells via a non-canonical pathway involving IL10 secretion (Han et al., 2020b) and to directly deplete the MDSC compartment of mouse mammary tumors, ultimately mediating an immunotherapeutic effect that can be enhanced by ICIs (Yin et al., 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Han et al., 2020b
Not checked in the free run.
- Premisecitation§ ll · p. 16
Venetoclax limits several features of CLL-associated immunosuppression in patients, including CTL exhaustion and NK-cell dysfunction.
“Of note, venetoclax limits several features of CLL-associated immunosuppression in patients, including CTL exhaustion and NK-cell dysfunction (de Weerdt et al., 2019) and does not reduce the number of peripheral T cells in patients with HR + BCL2 + metastatic breast cancer (Lok et al., 2019).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites de Weerdt et al., 2019 source
Not checked in the free run.
- Premisecitation§ ll · p. 16
Venetoclax does not reduce peripheral T-cell numbers in patients with HR+ BCL2+ metastatic breast cancer.
“Of note, venetoclax limits several features of CLL-associated immunosuppression in patients, including CTL exhaustion and NK-cell dysfunction (de Weerdt et al., 2019) and does not reduce the number of peripheral T cells in patients with HR + BCL2 + metastatic breast cancer (Lok et al., 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lok et al., 2019 source
Not checked in the free run.
- Premisecitation§ ll · p. 16
Pharmacological p53 reactivation downregulates IL6, an immunomodulatory cytokine linked to tumor progression.
“Additional immunostimulatory effects linked to pharmacological p53 reactivation in cancer cells include (but are not limited to) (1) downregulation of immunomodulatory cytokines linked to tumor progression, such as IL6 (Sahin et al., 2020); (2) upregulation of NKALs (Textor et al., 2011); and (3) establishment of cellular senescence linked to an immunostimulatory SASP that favors the recruitment”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sahin et al., 2020 source
Not checked in the free run.
- Premisecitation§ ll · p. 12
Immunocompetent mice whose T cells lack both Parp1 and Parp2 permit syngeneic tumor growth more than their littermates do.
“Interestingly, immunocompetent mice lacking both (but not either) Parp1 and Parp2 in T cells are more permissive for the growth of syngeneic tumors than their littermates (Moreno-Lama et al., 2020), pointing to an unrecognized role for PARPs in T-cell-dependent anticancer immunity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Moreno-Lama et al., 2020 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 16
ATR inhibitors synergize with radiation therapy and ICIs to control mouse hepatocellular carcinomas in immunocompetent hosts.
“Moreover, ATR inhibitors appear to offset the ability of RT to drive PD-L1 upregulation (Vendetti et al., 2018) and hence synergize with RT and ICIs in the control of mouse hepatocellular carcinomas established in immunocompetent hosts (Sheng et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sheng et al., 2020 source
Not checked in the free run.
- Premisecitation§ ll · p. 12
ATM cooperates with PARP1 to activate a non-canonical STING-dependent program that drives NFkB-dependent secretion of type I IFN and IL6, at least in immortalized human keratinocytes.
“ATM has been shown to cooperate with PARP1 in the activation of a non-canonical STING-dependent program converging on the NFk B-driven secretion of type I IFN and IL6 (at least in immortalized human keratinocytes) (Dunphy et al., 2018).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Dunphy et al., 2018 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 16
ATR inhibition potentiates olaparib-induced micronuclei formation and downstream CGAS signaling in BRCA2-deficient cancer cells.
“Moreover, ATR inhibition reportedly potentiates olaparib-driven micronuclei formation and consequent CGAS signaling in BRCA2 -deficient cancer cells (Schoonen et al., 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schoonen et al., 2019 source
Not checked in the free run.
- Premisecitation§ ll · p. 16
AURKA inhibition synergizes with MDM2 antagonism to induce senescence and immunological disease control in p53-competent melanomas.
“Finally, inhibition of the mitotic kinase aurora kinase a (AURKA) appears to synergize with an MDM2 antagonist in inducing senescence coupled to immunological disease control in p53-competent melanomas (Vilgelm et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vilgelm et al., 2015 source
Not checked in the free run.
- Premisecitation§ ll · p. 16
Pharmacological p53 reactivation upregulates NKALs.
“Additional immunostimulatory effects linked to pharmacological p53 reactivation in cancer cells include (but are not limited to) (1) downregulation of immunomodulatory cytokines linked to tumor progression, such as IL6 (Sahin et al., 2020); (2) upregulation of NKALs (Textor et al., 2011); and (3) establishment of cellular senescence linked to an immunostimulatory SASP that favors the recruitment”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Textor et al., 2011 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 16
Similar immune effects arise from accessing extranuclear CGAS-activating DNA via permeabilized mitochondria, through autophagy or BCL2 inhibition, and from delaying caspase-dependent apoptotic breakdown after mitochondrial permeabilization.
“Similar results have been obtained by actioning extranuclear sources of CGAS-activatory DNA such as permeabilized mitochondria (by autophagy or BCL2 inhibition) (Yamazaki et al., 2020), as well as by delaying the terminal breakdown of cancer cells undergoing caspasedependent apoptosis upon mitochondrial permeabilization (Buque ´ et al., 2019; Han et al., 2020a; Rodriguez-Ruiz et al., 2019).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ Review Cell · p. 16
ATR mediates strong immunosuppressive effects, especially after radiation therapy-induced DNA damage and G2/M arrest.
“Yet another DDR-relevant kinase, ATR, has been shown to mediate robust immunosuppressive effects, especially in the context of radiation therapy (RT)-driven DNA damage and consequent arrest in the G2/M phase of the cell cycle (Rodriguez-Ruiz et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rodriguez-Ruiz et al., 2020 source
Not checked in the free run.
- Interpretationcitation§ ll · p. 16
Inhibition of antiapoptotic BCL2 proteins produces robust immunostimulatory effects of therapeutic relevance.
“Although the clinical development of ABT-737 has been discontinued owing to on-target thrombocytopenia (Mason et al., 2007), these findings lend strong support to the notion that inhibition of antiapoptotic BCL2 proteins mediates robust immunostimulatory effects of therapeutic relevance.”
Quote in the paperSubstantial claim - Premisecitation§ Review Cell · p. 16
ATR inhibitors counteract the ability of radiation therapy to increase PD-L1.
“Moreover, ATR inhibitors appear to offset the ability of RT to drive PD-L1 upregulation (Vendetti et al., 2018) and hence synergize with RT and ICIs in the control of mouse hepatocellular carcinomas established in immunocompetent hosts (Sheng et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vendetti et al., 2018 source
Not checked in the free run.
- Premisecitation§ ll · p. 16
ABT-737 drives type I IFN secretion by cancer cells downstream of mtDNA-driven CGAS activation, especially when caspases are inhibited.
“Finally, ABT-737 (an experimental inhibitor of multiple BCL2 family members) is known for its ability to drive robust type I IFN secretion by cancer cells downstream of mtDNA-driven CGAS activation, especially in the context of caspases inhibition (Rongvaux et al., 2014; White et al., 2014).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ ll · p. 12
In platinum-resistant ovarian cancer patients given PARP inhibitors plus ICIs, higher circulating type I IFN- and IFNG-related cytokines and malignant-cell PD-L1 expression are associated with better disease outcome.
“Moreover, increased circulating levels of type I IFN- and IFNG-related cytokines as well as PD-L1 expression in malignant cells have been associated with favorable disease outcome in patients with platinum-resistant ovarian cancer receiving PARP inhibitors plus ICIs (F € arkkil € a et al., 2020; Lampert et al., 2020).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites F € arkkil € a et al., 2020
Not checked in the free run.
- cites Lampert et al., 2020 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 17
The abundance of PD-L1+ IDO1+ TAMs negatively correlates with intratumoral NK cells and trastuzumab sensitivity in HER2+ breast cancer patients.
“Moreover, the abundance of PD-L1 + IDO1 + TAMs has been negatively correlated with the intratumoral abundance of NK cells and sensitivity to trastuzumab in a cohort of patients with HER2 + breast cancer (Su et al., 2018), and the local delivery of IL21 promotes the therapeutic activity of HER2-targeting mAbs in preclinical models of the disease as it favors TAM repolarization toward an immunostim”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Su et al., 2018
Not checked in the free run.
- Premisecitation§ Review Cell · p. 17
ADCP may be accompanied by macrophage polarization toward an M2-like immunosuppressive phenotype.
“HER2-targeting mAbs also elicit antibody-dependent cellular phagocytosis (ADCP), involving the clearance of antibodybound tumor cells by macrophages (Shi et al., 2015), a phenomenon that may be accompanied by macrophage polarization towardanM2-like immunosuppressive phenotype (Su et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Su et al., 2018
Not checked in the free run.
- Premisecitation§ Review Cell · p. 17
Progressive loss of HER2-targeting CD4+ TH1 cells facilitates HER2-driven mammary carcinogenesis.
“In line with this notion, the progressive loss of HER2-targeting CD4 + TH1 cells reportedly facilitates HER2-driven mammary carcinogenesis (Datta et al., 2015a), and multiple immunotherapeutic agents, including DC-based vaccines (Datta et al., 2015b; Linch et al., 2016), TLR2 agonists (Lu et al., 2011), recombinant IL21 (Roda et al., 2006), and PD-L1 blockers (Mittal et al., 2019), can be”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Datta et al., 2015a
Not checked in the free run.
- Premisecitation§ HER2, EGFR, VEGFA, AND TGFb INHIBITORS · p. 17
HER2-targeted mAbs engage some degree of CD8+ and CD4+ T-cell-dependent HER2-specific immune responses.
“HER2-targeted mAbs also appear to engage some degree of CD8 + and CD4 + T-cell-dependent HER2-specific immune responses (Mittal et al., 2016; Mortenson et al., 2013; Park et al., 2010; Taylor et al., 2007), at least in part reflecting improved antigen presen-”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ HER2, EGFR, VEGFA, AND TGFb INHIBITORS · p. 17
TGFb blockers have not yet entered clinical routine.
“Conversely, TGFb blockers have not yet entered the clinical routine (Derynck et al., 2020), although both TGFb traps and TGFb receptor 1 (TGFBR1) inhibitors continue to be scrutinized for safety and efficacy in phase I-II clinical trials (source https://clinicaltrials. gov/).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Derynck et al., 2020
Not checked in the free run.
- Premisecitation§ Review Cell · p. 17
PD-L1 and IDO1 blockade improves the therapeutic activity of HER2-targeting mAbs in mouse models of HER2+ breast cancer.
“Consistent with this, PD-L1 and IDO1 blockade improves the therapeutic activity of HER2-targeting mAbs in mouse models of HER2 + breast cancer (Su et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Su et al., 2018
Not checked in the free run.
- Premisecitation§ HER2, EGFR, VEGFA, AND TGFb INHIBITORS · p. 17
The ADCC mechanism applies to the humanized HER2-specific mAbs trastuzumab and pertuzumab.
“This applies to the humanized HER2-specific mAbs trastuzumab and pertuzumab (Misumi et al., 2018; Park et al., 2010; Stagg et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ HER2, EGFR, VEGFA, AND TGFb INHIBITORS · p. 17
HER2-, EGFR-, and VEGFA-specific agents have been licensed for various oncological indications.
“Over the past two decades, a number of mAbs and TKIs have been developed to target these proteins or their binding partners, and some of these molecules, including HER2-, EGFR-, and VEGFA-specific agents, have been licensed for use in a variety of oncological indications (Apte et al., 2019; Oh and Bang, 2020; Pao and Chmielecki, 2010).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ Review Cell · p. 17
HER2-targeting mAbs elicit ADCP, clearing antibody-bound tumor cells by macrophages.
“HER2-targeting mAbs also elicit antibody-dependent cellular phagocytosis (ADCP), involving the clearance of antibodybound tumor cells by macrophages (Shi et al., 2015), a phenomenon that may be accompanied by macrophage polarization towardanM2-like immunosuppressive phenotype (Su et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shi et al., 2015 source
Not checked in the free run.
- Interpretationreasoning§ ll · p. 17
Agents targeting molecular pathways downstream of DNA damage produce therapeutically relevant immunomodulation.
“Altogether, these observations exemplify therapeutically relevant immunomodulation by various agents targeting the molecular pathways that emanate from DNA damage.”
Quote in the paperSubstantial claim - Premisecitation§ HER2, EGFR, VEGFA, AND TGFb INHIBITORS · p. 17
VEGFA is critical for tumor-driven neoangiogenesis.
“Indeed, while ERBB2 gene amplifications and gain-of-function EGFR mutations support the proliferation of various cancer cell types (Oh and Bang, 2020; Pao and Chmielecki, 2010), VEGFA is critical for tumor-driven neoangiogenesis (Apte et al., 2019) and TGFb promotes the establishment of a fibrotic microenvironment that is poorly permissive to access by therapeutics (Derynck et al., 2020).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Apte et al., 2019 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 17
Local IL21 delivery promotes HER2-targeting mAb activity in preclinical models by repolarizing TAMs toward an immunostimulatory phenotype.
“Moreover, the abundance of PD-L1 + IDO1 + TAMs has been negatively correlated with the intratumoral abundance of NK cells and sensitivity to trastuzumab in a cohort of patients with HER2 + breast cancer (Su et al., 2018), and the local delivery of IL21 promotes the therapeutic activity of HER2-targeting mAbs in preclinical models of the disease as it favors TAM repolarization toward an immunostim”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Xu et al., 2015
Not checked in the free run.
- Premisenone given§ HER2, EGFR, VEGFA, AND TGFb INHIBITORS · p. 17
HER2, EGFR, VEGFA, and TGFb inhibitors have been shown to mediate immunomodulatory effects of therapeutic relevance.
“All these agents have been shown to mediate immunomodulatory effects of therapeutic relevance (Table 4).”
Quote in the paperNot a substantial claim - Premisecitation§ HER2, EGFR, VEGFA, AND TGFb INHIBITORS · p. 17
The therapeutic efficacy of multiple mAbs targeting plasma membrane receptors in oncogenesis stems at least partly from bridging malignant cells and FcγR-expressing immune effector cells, leading to ADCC.
“The therapeutic efficacy of multiple mAbs targeting plasma membrane receptors involved in oncogenesis stems (at least in part) from their ability to bridge malignant cells and immune effector cells expressing Fc gamma receptors (Fc g Rs), culminating in antibody-dependent cellular cytotoxicity (ADCC) (Ferris et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ferris et al., 2010 source
Not checked in the free run.
- Premisecitation§ HER2, EGFR, VEGFA, AND TGFb INHIBITORS · p. 17
TGFb promotes a fibrotic microenvironment that is poorly permissive to therapeutic access.
“Indeed, while ERBB2 gene amplifications and gain-of-function EGFR mutations support the proliferation of various cancer cell types (Oh and Bang, 2020; Pao and Chmielecki, 2010), VEGFA is critical for tumor-driven neoangiogenesis (Apte et al., 2019) and TGFb promotes the establishment of a fibrotic microenvironment that is poorly permissive to access by therapeutics (Derynck et al., 2020).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Derynck et al., 2020
Not checked in the free run.
- Premisecitation§ Review Cell · p. 18
Gefitinib enhances uptake of tumor material by DCs independently of ICD.
“enhanced uptake of tumor material by DCs independent of ICD”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nigro et al., 2019 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 19
Vactosertib downregulates PD-L1 in melanoma in vivo in the context of delayed TGFb inhibition, relieving immunosuppression.
“PD-L1 downregulation by melanoma in vivo , in the context of delayed TGF b inhibition”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhao et al., 2018 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 20
VEGFA-neutralizing mAbs and VEGFR-targeting agents mediate immunostimulatory effects independent of ADCC and ADCP, largely due to VEGFA's role in cancer-related immunosuppression.
“VEGFA-neutralizing mAbs as well as agents targeting VEGFA receptors (VEGFRs) mediate immunostimulatory effects independent of ADCC and ADCP, largely reflecting the key role of VEGFA in the establishment of cancer-related immunosuppression”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yang et al., 2018 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 20
Bevacizumab and other VEGFA signaling suppressors are associated with improved DC maturation in preclinical cancer models.
“improved DC maturation”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Osada et al., 2008 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 19
M2-like TAM accumulation and related PD-L1 expression correlate with poor cetuximab response in locally advanced neck squamous cell carcinoma.
“The latter effect has been correlated with poor responses to cetuximab in patients with locally advanced neck squamous cell carcinoma”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Li et al., 2015
Not checked in the free run.
- Premisecitation§ Review Cell · p. 20
VEGFA signaling is directly involved in TREG cell expansion.
“VEGFA signaling is directly involved in TREG cell expansion”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Terme et al., 2013 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 21
TGFb inhibition boosts focal RT-driven immunostimulation in preclinical mouse models of breast carcinoma, especially when combined with systemic ICIs.
“TGFb inhibition has been shown to potently boost focal RT-driven immunostimulation in preclinical mouse models of breast carcinoma, especially when combined with systemic ICIs”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vanpouille-Box et al., 2015 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 20
Bevacizumab and other VEGFA signaling suppressors such as sunitinib are associated with increased tumor infiltration by activated TEFF cells and depletion of TREG and TAMs in preclinical cancer models.
“increased tumor infiltration by activated TEFF cells coupled to TREG (and TAM) depletion”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ Review Cell · p. 21
TGFb promotes PD-1 expression by T cells.
“promote PD-1 expression by T cells”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Batlle and Massague, 2019 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 20
VEGFA signaling is directly involved in expression of co-inhibitory receptors including PD-1 by CD8+ CTLs.
“expression of co-inhibitory receptors, including PD-1 by CD8 + CTLs”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Voron et al., 2015 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 21
TGFb is involved in immunological exclusion, where cancer cells co-opt cancer-associated fibroblasts to prevent tumor infiltration by immune effector cells.
“TGFb is intimately involved in the establishment of immunological exclusion, an active process through which cancer cells co-opt cancer-associated fibroblasts to prevent tumor infiltration by immune effector cells”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Galluzzi et al., 2018 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 20
Accumulation of immunosuppressive cells including TAMs is linked to resistance to VEGFA-targeting antibodies in mouse models of ovarian cancer.
“the accumulation of immunosuppressive cells, including TAMs, has been linked with resistance to VEGFA-targeting antibodies in mouse models of ovarian cancer”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dalton et al., 2017 source
Not checked in the free run.
- Interpretationreasoning§ Review Cell · p. 20
T-cell recruitment and activation downstream of VEGFA inhibition likely stems from non-lymphoid TME components.
“suggesting that T-cell recruitment and activation downstream of VEGFA inhibition likely stems from non-lymphoid TME components”
Quote in the paperSubstantial claim - Interpretationreasoning§ Review Cell · p. 21
Combinatorial regimens involving one or multiple ICIs may be required to fully harness the potential of TGFb inhibitors in the clinic.
“combinatorial regimens involving one or multiple ICIs may be required to fully harness the potential of TGFb inhibitors in the clinic”
Quote in the paperSubstantial claim - Premisecitation§ Review Cell · p. 19
EGFR inhibitors promote resolution of neutrophilic inflammation.
“EGFR inhibitors have also been shown to promote the resolution of neutrophilic inflammation”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rahman et al., 2019 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 20
Endothelial cells exposed to various VEGFA inhibitors express increased adhesion molecules involved in T-cell extravasation, PD-L1, and pro-inflammatory cytokines.
“ECs exposed to various VEGFA inhibitors have been shown to express increased levels of adhesion molecules involved in T-cell extravasation, PD-L1, and pro-inflammatory cytokines”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation§ Review Cell · p. 20
Superior therapeutic response with VEGFA-targeting agents plus PD-L1 inhibitors may involve an unsuspected vascular component.
“These findings suggest that the superior therapeutic response achieved with VEGFA-targeting agents plus PD-L1 inhibitors may involve an unsuspected vascular component”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Allen et al., 2017 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 20
Bevacizumab and other VEGFA signaling suppressors are associated with PD-L1 downregulation by malignant and myeloid cells in preclinical cancer models.
“PD-L1 downregulation by malignant and myeloid cells”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ Review Cell · p. 21
Metastatic breast cancer patients receiving fresolimumab with hypofractionated RT exhibited an expanded peripheral CD8+ memory T-cell pool.
“patients with metastatic breast cancer receiving fresolimumab, a TGFb -targeting mAb, in the context of hypofractionated RT exhibited an expanded CD8 + memory T-cell pool in the periphery”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Formenti et al., 2018a
Not checked in the free run.
- Premisecitation§ Review Cell · p. 20
VEGFA levels inversely correlate with signatures of CD8+ CTL infiltration in breast cancer biopsies and preclinical mammary and colorectal carcinoma models.
“transcriptomic analyses revealed an inverse correlation between VEGFA levels and signatures of CD8 + CTL infiltration in biopsies from breast cancer patients as well as in preclinical models of mammary and colorectal carcinoma”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Palazon et al., 2017 source
Not checked in the free run.
- cites Wang et al., 2020c
Not checked in the free run.
- Premisecitation§ Review Cell · p. 19
Independent investigators have not reproduced the finding that gefitinib upregulates NKALs in NSCLC cells.
“similar findings have not been reproduced by independent investigators”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Okita et al., 2015 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 21
Genetic signatures linked to TGFb signaling and stromal remodeling are associated with poor disease outcome and immunotherapy failure across multiple human cancers.
“genetic signatures linked to TGFb signaling and stromal remodeling are associated with poor disease outcome and immunotherapy failure across multiple human cancers”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chakravarthy et al., 2018 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 19
Multiple EGFR-targeting TKIs decrease PD-L1 expression by NSCLC cells by interrupting NFkB and IL6 signaling.
“multiple EGFR-targeting TKIs efficiently decrease PD-L1 expression by NSCLC cells, reflecting their ability to interrupt NFk Band IL6 signaling”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ Review Cell · p. 20
VEGFA deletion in T cells facilitates growth of mouse B16 melanomas.
“VEGFA deletion in T cells facilitates the growth of mouse B16 melanomas”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Palazon et al., 2017 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 21
TGFb upregulates PD-L1 on malignant and myeloid TME compartments.
“upregulate PD-L1 on malignant and myeloid TME compartments”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Batlle and Massague, 2019 source
Not checked in the free run.
- Interpretationcitation§ Review Cell · p. 21
Treatment sequencing may be a key determinant for success.
“treatment sequencing may be a key determinant for success”
Quote in the paperSubstantial claim - Premisecitation§ Review Cell · p. 22
DNMT inhibitors are consistently linked to better MHC class I presentation.
“various DNMT inhibitors have been consistently associated with improved MHC class I presentation”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ Review Cell · p. 22
EZH2 inhibition restores CD58 expression, a molecule commonly downregulated in lymphoma cells to support immune evasion.
“restored expression of CD58 (which is generally downregulated in lymphoma cells in support of immunoevasion)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Otsuka et al., 2020 source
Not checked in the free run.
- Interpretationcitation§ Review Cell · p. 22
The immunosuppressive effects of ibrutinib may not stem from BTK inhibition, as shown with the more specific BTK inhibitor zanubrutinib.
“albeit such immunosuppressive effects may not stem from BTK inhibition (as demonstrated with the more specific second-generation BTK inhibitor zanubrutinib)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Flinsenberg et al., 2020 source
Not checked in the free run.
- Interpretationreasoning§ Review Cell · p. 22
The exact effect of pharmacological EZH2 inhibition on anticancer immunity is still not fully known.
“the precise impact of pharmacological EZH2 inhibition on anticancer immunity remains to be fully elucidated”
Quote in the paperSubstantial claim - Interpretationreasoning§ Review Cell · p. 21
HER2, EGFR, VEGFA, and TGFb inhibitors have multipronged immunostimulatory effects.
“these observations highlight the multipronged immunostimulatory effects of HER2, EGFR, VEGFA, and TGFb inhibitors”
Quote in the paperSubstantial claim - Premisecitation§ OTHERS · p. 21
Ibrutinib favors depletion of MDSCs and their differentiation toward a mature DC-like phenotype with MHC class II upregulation and improved antigen presentation.
“ibrutinib reportedly favors the depletion of MDSCs coupled to their differentiation toward a mature DClike phenotype associated with MHC class II upregulation and improved antigen-presentation capacity”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ Review Cell · p. 22
Targeting DNMT1 with shRNAs or blocking DNMTs with decitabine or guadecitabine promotes CXCL9 and CXCL10 secretion in breast, lung, and ovarian carcinoma models.
“epigenetic reprogramming with shRNAs targeting DNA methyltransferase 1 (DNMT1) or pan-DNMT blockers like decitabine and guadecitabine has been shown to resemble EZH2 inhibition in its capacity to promote CXCL9 and CXCL10 secretion in various models of breast, lung, and ovarian carcinoma”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ Review Cell · p. 22
Vorinostat requires an intact immune system to exert therapeutic activity against hematological and solid malignancies in mice.
“an intact immune system is required for the prototypic HDAC inhibitor vorinostat to mediate therapeutic activity against hematological and solid malignancies in mice”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites West et al., 2013 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 22
EZH2 inhibition restores TH1 cytokine expression.
“and TH1 cytokines”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Peng et al., 2015 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 21
Administering TGFb inhibitors after acquired PD-1 resistance mediates robust therapeutic effects.
“the administration of TGFb inhibitors once acquired PD-1 resistance has emerged mediates robust therapeutic effects”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhao et al., 2018 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 21
Upfront TGFb inhibition promotes resistance to PD-1 blockers by favoring MMP9-driven PD-L1 cleavage.
“upfront TGFb inhibition appears to promote at least some degree of resistance to PD1 blockers by favoring matrix metallopeptidase 9 (MMP9)driven PD-L1 cleavage”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhao et al., 2018 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 22
Ibrutinib may limit CTL and NK-cell proliferation and effector functions in response to activating stimuli.
“ibrutinib has also been suggested to limit CTL and NK-cell proliferation and effector functions in response to activating stimuli”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ Review Cell · p. 22
The EZH2 inhibitor GSK126 promotes MDSC expansion and immunosuppressive functions.
“EZH2 inhibition with GSK126 reportedly favors MDSC expansion and immunosuppressive functions”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Huang et al., 2019 source
Not checked in the free run.
- Premisecitation§ OTHERS · p. 21
Most clinically employed targeted anticancer drugs mediate at least some degree of immunomodulation.
“most of these clinically employed drugs mediate at least some degree of immunomodulation”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Table 5
Not checked in the free run.
- Premisecitation§ Review Cell · p. 22
Short hairpin RNAs targeting EZH2 impair the ability of CD8+ cytotoxic T lymphocytes to mount strong immune responses.
“short hairpin RNAs (shRNAs) targeting EZH2 compromise the ability of CD8 + CTLs to mount robust immune responses”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zhao et al., 2016 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 22
HDAC-targeting drugs promote NKAL expression by melanoma cells.
“HDAC-targeting agents favor NKAL expression by melanoma cells”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites López-Cobo et al., 2018 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 22
In ovarian cancer patients, tumor infiltration by EZH2+CD8+ cells correlates with a positive prognosis.
“correlating with a positive prognostic impact for tumor infiltration by EHZ2 + CD8 + cells in patients with ovarian cancer”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zhao et al., 2016 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 22
HDAC inhibitors produce similar immune-related findings in syngeneic mouse melanoma models after epigenetic reprogramming.
“Similar findings have been documented in syngeneic mouse models of melanoma subjected to epigenetic reprogramming with HDAC inhibitors”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ Review Cell · p. 22
EZH2 inhibition is linked to immunostimulation that follows improved antigen presentation by cancer cells.
“EZH2 inhibition, is associated with multipronged immunomodulatory effects, encompassing immunostimulation downstream of improved antigen presentation by cancer cells”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation§ Review Cell · p. 22
The immunogenic cell death induced by crizotinib can be exploited therapeutically by adding a PD-1-targeting monoclonal antibody.
“could be actioned therapeutically with PD-1-targeting mAb”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liu et al., 2019 source
Not checked in the free run.
- Interpretationcitation§ Review Cell · p. 22
The crizotinib-associated immune changes in preclinical NSCLC models are thought to result from strong immunogenic cell death induction by crizotinib.
“an effect that presumably reflected the ability of crizotinib to robustly drive ICD”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liu et al., 2019 source
Not checked in the free run.
- Premisecitation§ ll · p. 22
CD20-targeting monoclonal antibodies such as rituximab, obinutuzumab, ocaratuzumab, and ofatumumab stimulate immunity through ADCC, ADCP, or complement-dependent cytotoxicity.
“CD20-targeting mAbs such as rituximab, obinutuzumab, ocaratuzumab, and ofatumumab”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning§ CONCLUDING REMARKS · p. 22
Targeted anticancer agents that have entered clinical evaluation and received regulatory approval generally produce immunostimulatory effects.
“the targeted agents that have entered clinical evaluation and obtained regulatory approval for use in cancer patients generally mediate immunostimulatory effects”
Quote in the paperNot a substantial claim - Premisecitation§ ll · p. 22
Many monoclonal antibodies that target malignant cells stimulate immunity through ADCC, ADCP, or complement-dependent cytotoxicity.
“a variety of mAbs targeting malignant cells mediate immunostimulation upon the engagement of ADCC, ADCP, or complement-dependent cytotoxicity”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ Review Cell · p. 22
DNMT inhibitors are consistently linked to derepression of endogenous retroviral elements and strong type I and type III interferon signaling.
“derepression of endogenous retroviral elements coupled to robust type I and type III IFN signaling”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ ll · p. 22
CD33- and CD58-targeting monoclonal antibodies stimulate immunity through ADCC, ADCP, or complement-dependent cytotoxicity.
“as well as CD33- and CD58-targeting mAbs”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ CONCLUDING REMARKS · p. 22
Some targeted anticancer agents promote immune responses that support efficacy, for example EGFR inhibitors inducing immunogenic cell death.
“as they favor immune responses that support efficacy (e.g., ICD induction by EGFR inhibitors)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pozzi et al., 2016 source
Not checked in the free run.
- Premisecitation§ Box 2. ICIs for cancer therapy · p. 26
Immune effector cells, especially activated CD4+ and CD8+ T cells, express co-inhibitory receptors that are crucial for ending ongoing immunity and maintaining peripheral tolerance.
“Immuneeffector cells, especially (but not only) activated CD4 + and CD8 + T cells, express a panel of co-inhibitory receptors that are key for the extinguishment of ongoing immunity and the preservation of peripheral tolerance”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sharma and Allison, 2020
Not checked in the free run.
- Premisecitation§ ll · p. 22
In the CD34+ compartment of myelodysplastic syndrome patients, decitabine upregulates several immunosuppressive mediators, including CTLA4, PD-1, and PD-1 ligands.
“decitabine to promote the upregulation of multiple immunosuppressive mediators, including CTLA4, PD-1, and its ligands, as demonstrated in the CD34 + compartment of patients with myelodysplastic syndromes”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yang et al., 2014 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 25
Imatinib, although designed to inhibit the ABL1 kinase domain, inhibits several clinically relevant kinases.
“Imatinib, which was designed to target the kinase domain of ABL1 for inhibiting constitutive signaling from the BCR-ABL1chimera,turned out to inhibit a variety of clinically relevant kinases”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Carlisle et al., 2020 source
Not checked in the free run.
- Premisecitation§ ll · p. 22
DNMT inhibitors are consistently linked to tumor microenvironment reconfiguration that supports anticancer immunity or increases sensitivity to CTLA4 or PD-1 blockade.
“reconfiguration of the TME (Luo et al., 2018; Travers et al., 2019; Wanget al., 2015; Yu et al., 2019) in support of anticancer immunity or increased sensitivity to CTLA4-or PD-1 blockage”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation§ ll · p. 22
FcγR engagement on NK cells by unbound tumor-specific monoclonal antibodies may represent an immunological resistance mechanism to monoclonal antibody-based targeted anticancer therapies.
“potentially identifying an immunological mechanism of resistance to targeted anticancer therapies based on mAbs”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Capuano et al., 2015 source
Not checked in the free run.
- Premisecitation§ Review Cell · p. 22
DNMT inhibitors are consistently linked to upregulation of tumor-associated antigens.
“upregulation of TAAs”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ ll · p. 22
The CD22-specific agent epratuzumab stimulates immunity through ADCC, ADCP, or complement-dependent cytotoxicity.
“the CD22-specific drug epratuzumab”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Carnahan et al., 2007 source
Not checked in the free run.
- Interpretationcitation§ ll · p. 22
The therapeutic cooperativity between DNMT inhibitors and immune checkpoint inhibitors may reflect decitabine-mediated upregulation of immunosuppressive mediators.
“Potentially, such a therapeutic cooperativity reflects the ability of decitabine to promote the upregulation of multiple immunosuppressive mediators”
Quote in the paperNot a substantial claim - Premisecitation§ ll · p. 22
The CD52-directed monoclonal antibody alemtuzumab stimulates immunity through ADCC, ADCP, or complement-dependent cytotoxicity.
“the CD52-directed mAb alemtuzumab”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zhang et al., 2018c
Not checked in the free run.
- Premisecitation§ ll · p. 22
FcγR engagement on NK cells by unbound tumor-specific monoclonal antibodies limits NK-cell responsiveness to stimulation.
“Fc g R engagement on NK cells by unbound tumor-specific mAbs reportedly limits NK-cell responsiveness to stimulation”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Capuano et al., 2015 source
Not checked in the free run.
- Premisecitation§ Box 2. ICIs for cancer therapy · p. 26
When used alone, immune checkpoint inhibitors produce durable clinical responses in only a small fraction of patients, about 15% to 30% depending on the cancer setting.
“ICIs employed as standalone immunotherapeutic agents have been shown to induce highly durable clinical responses, but only in a relatively small (15%-30%, depending on oncological setting) fraction of patients”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ribas and Wolchok, 2018
Not checked in the free run.
- Interpretationreasoning§ Review Cell · p. 25
In many cases, the mechanisms behind divergent immunomodulatory effects of targeted anticancer agents remain unclear.
“in many others the underlying mechanisms remain obscure”
Quote in the paperSubstantial claim - Premisenone given§ Cell · p. 27
Radiation therapy frequently induces immunogenic cell death in a context where latent TGF-beta is activated.
“Immunogenic cell death induction by radiation therapy (RT) often occurs in the context of latent transforming growth factor beta (TGFb ) activation”
Quote in the paperSubstantial claim - Premisecitation§ Box 2. ICIs for cancer therapy · p. 26
Preclinical data suggest that TGFb blockers may reduce immune-cell exclusion from the tumor microenvironment, enabling responsiveness to PD-1 or PD-L1 checkpoint inhibitors.
“but also to limit the exclusion of immune cells from the TME, hence enabling (at least some) responsiveness to ICIs targeting PD-1 or PD-L1”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation§ Box 2. ICIs for cancer therapy · p. 26
The limited responses to radiotherapy plus fresolimumab were at least partly due to PD-1-dependent functional defects in the T-cell compartment at baseline.
“at least in part reflecting PD-1dependent functional defects of the T-cell compartment at baseline”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Formenti et al., 2019 source
Not checked in the free run.
- Interpretationreasoning§ Cell · p. 27
Combining radiation therapy with TGF-beta blockers could be advantageous for patients.
“suggesting that RT could advantageously be combined with TGFb blockers in patients”
Quote in the paperSubstantial claim - Interpretationreasoning§ Cell · p. 27
Chemotherapeutic regimens that deplete myeloid-derived suppressor cells or limit their immunosuppressive functions are promising partners to combine with EZH2 inhibitors.
“Thus, chemotherapeutic regimens that deplete MDSCs and/or limit their immunosuppressive functions, such as 5-fluorouracil (5-FU)- or gemcitabine-based chemotherapy, stand out as promising combinatorial partners for EZH2 inhibitors.”
Quote in the paperSubstantial claim - Interpretationcitation§ Review Cell · p. 25
Genetic, epigenetic, or metabolic heterogeneity may critically affect the immunomodulatory effects of targeted anticancer agents, especially in vivo.
“potentially neglected and/or hardly controllable genetic, epigenetic, or metabolic sources of heterogeneity may have a critical impact, especially in vivo”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hausser and Alon, 2020
Not checked in the free run.
- Interpretationreasoning§ Cell · p. 27
Immune checkpoint inhibitors targeting PD-1 or PD-L1 are promising partners to combine with CDK4/CDK6 inhibitors to at least partly overcome PD-L1-dependent immunosuppression.
“Thus, ICIs targeting PD-1 or PD-L1 stand out as promising combinatorial partners for CDK4/CDK6 inhibitors to circumvent (at least partially) PD-L1-dependent immunosuppression.”
Quote in the paperSubstantial claim - Premisecitation§ Box 2. ICIs for cancer therapy · p. 26
Radiotherapy stimulates PD-L1 upregulation on cells in the myeloid compartment.
“stimulate the upregulation of PD-L1 on cells from the myeloid compartment”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Prima et al., 2017 source
Not checked in the free run.
- Interpretationreasoning§ Review Cell · p. 25
Most targeted anticancer drugs discussed in the paper have both immunostimulatory and immunosuppressive effects, depending on the experimental setting.
“Most of the drugs discussed herein have been associated with both immunostimulatory and immunosuppressive effects, depending on the specific experimental scenario”
Quote in the paperSubstantial claim - Interpretationcitation§ Box 2. ICIs for cancer therapy · p. 26
Radiotherapy-induced PGE2 secretion and myeloid PD-L1 upregulation could potentially support tumor repopulation when immunosuppression is present.
“which otherwise would potentially support tumor repopulation in the context of accrued immunosuppression”
Quote in the paperSubstantial claim - Interpretationcitation§ Box 2. ICIs for cancer therapy · p. 26
Whether conventional chemotherapeutics or radiotherapy can further boost the efficacy of combinations between targeted anticancer agents and immunotherapeutics has not been thoroughly studied.
“whether the efficacy of such combinations can be further boosted with conventional chemotherapeutics or RT (both of which can also mediate clinically relevant immunomodulatory effects) (Galluzzi et al., 2020a; Rodriguez-Ruiz et al., 2020) has not been thoroughly investigated”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Galluzzi et al., 2020a
Not checked in the free run.
- cites Rodriguez-Ruiz et al., 2020 source
Not checked in the free run.
- Premisecitation§ Box 2. ICIs for cancer therapy · p. 26
In a clinical trial of patients with metastatic breast cancer, responses to radiotherapy combined with the TGFb blocker fresolimumab were limited.
“clinical responses to RT combined with the TGFb blocker fresolimumab were limited in a clinical trial enrolling patients with metastatic breast cancer”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Formenti et al., 2018a
Not checked in the free run.
- Interpretationreasoning§ Review Cell · p. 25
Proteins that support oncogenesis also affect the ability of cancer cells to deliver immunostimulatory or immunosuppressive signals.
“implying that various proteins that support oncogenesis also influence the ability of neoplastic cells to deliver immunostimulatory or immunosuppressive signals”
Quote in the paperSubstantial claim - Premisecitation§ Review Cell · p. 25
Active CDK4/CDK6 signaling restricts DNMT1-driven expression of endogenous retroviral elements that would otherwise promote type III interferon secretion.
“active CDK4/CDK6 signaling limits the ability of DNMT1 to drive the expression of endogenous retroviral elements that would otherwise promote type III IFN secretion”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Goel et al., 2017 source
Not checked in the free run.
- Premisecitation§ Box 2. ICIs for cancer therapy · p. 26
Radiotherapy promotes secretion of mitogens such as prostaglandin E2 from dying cells.
“the ability of RT to promote the secretion of mitogens such as prostaglandin E2 (PGE2) from dying cells”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Huang et al., 2011 source
Not checked in the free run.
- Premisecitation§ Box 2. ICIs for cancer therapy · p. 26
Preclinical data suggest that TGFb blockers may enhance the ability of radiotherapy to initiate systemic anticancer immune responses.
“preclinical data suggest that TGFb blockers may be useful not only to boost the ability of RT to initiate anticancer immune responses with systemic outreach”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vanpouille-Box et al., 2015 source
Not checked in the free run.
- Interpretationreasoning§ Cell · p. 27
Adding an immune checkpoint inhibitor against PD-1 or PD-L1 would be beneficial in that setting.
“suggesting a benefit for the addition of an immune checkpoint inhibitor (ICI) specific for PD-1 or its ligand CD274 (best known as PD-L1)”
Quote in the paperSubstantial claim - Premisenone given§ Cell · p. 27
In metastatic breast cancer, dysfunction of PD-1-dependent T cells at baseline appears to block optimal efficacy.
“In the context of metastatic breast cancer, however, programmed cell death 1 (PDCD1, best known as PD-1)-dependent T-cell dysfunction at baseline appears to prevent optimal efficacy”
Quote in the paperNot a substantial claim - Interpretationcitation§ Review Cell · p. 25
The CDK4/CDK6-DNMT1-endogenous retroviral element-type III interferon pathway can be targeted with clinically used CDK4/CDK6 inhibitors.
“a pathway that can be actioned with clinically employed CDK4/ CDK6 inhibitors”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Goel et al., 2017 source
Not checked in the free run.
- May combine two claims. 96
- Classified as probably not a substantial claim. 11
- The quote only partly states this claim. 6
May combine two claims.
Premisecitation§ Box 1. ICD in cancer therapy · p. 2Preclinical tumor models show that various clinically relevant anticancer treatments-conventional chemotherapy, radiation, and targeted agents-can trigger bona fide ICD and start the cancer-immunity cycle.
“a variety of clinically relevant anticancer interventions including conventional chemotherapeutics (Galluzzi et al., 2020a), radiation therapy (RT) (Rodriguez-Ruiz et al., 2020), and targeted anticancer agents (see main text) have been shown to elicit bona fide ICD and hence jumpstart the cancer-immunity cycle (Chen and Mellman, 2017) in preclinical tumor models.”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisereasoning§ Box 1. ICD in cancer therapy · p. 2Targeted anticancer agents can yield net immune stimulation by increasing pro-inflammatory cytokine release or by reducing immunosuppressive factors.
“targeted anticancer agents can mediate net immunostimulatory effects by promoting the secretion of pro-inflammatory cytokines, or by limiting the release or activity of immunosuppressive factors.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ Box 1. ICD in cancer therapy · p. 2Targeted anticancer drugs can modulate immunity through interactions with cancer cells or with immune cells.
“The immunomodulatory activity of targeted anticancer agents can originate from the interaction of the drug with cancer cells, as well as from the ability of the drug to interact with, and alter the function of, immune cells (Galluzzi et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Galluzzi et al., 2015 source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
Interpretationreasoning§ Box 1. ICD in cancer therapy · p. 2The ability of targeted anticancer agents to modulate immunity justifies developing combinations with immunotherapy.
“the capacity of targeted anticancer agents to mediate immunomodulatory effects provides a strong rationale to develop combinatorial regimens involving immunotherapy.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ Review Cell · p. 6In that HER2+ model, ICIs do not improve targeted therapy efficacy unless cabozantinib is added, which creates a TME dominated by immune effector cells rather than MDSCs.
“ICIs fail to improve the efficacy of targeted anticancer agents, unless combined with the multitargeted tyrosine kinase inhibitor (TKI) cabozantinib, resulting in the establishment of a tumor microenvironment (TME) dominated by immune effector cells (rather than MDSCs)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wang et al., 2019a
Not checked in the free run.
May combine two claims.
Premisecitation§ ll · p. 6CDK7 inhibition in mice with syngeneic lung cancers increases immune effector cell infiltration and can be combined successfully with PD-1-targeting ICIs.
“CDK7 inhibition in mice bearing syngeneic lung cancers promotes tumor infiltration by immune effector cells and can be successfully combined with ICIs targeting PD-1 (Wang et al., 2020b; Zhang et al., 2020a).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Wang et al., 2020b
Not checked in the free run.
- cites Zhang et al., 2020a
Not checked in the free run.
May combine two claims.
Premisecitation§ ll · p. 6Dinaciclib induces ICD and type I IFN signaling in mouse colorectal cancer models, promoting dendritic cell activation and CD8+ T-cell recruitment that can be exploited with PD-1-specific ICIs.
“dinaciclib promotes immunogenic cell death (ICD) along with robust type I IFN signaling (and despite PD-L1 upregulation in this setting) in mouse models of colorectal cancer (CRC), ultimately favoring dendritic cell (DC) activation and recruitment of CD8 + T cells that can be actioned with ICIs specific for PD-1”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hossain et al., 2018 source
Not checked in the free run.
May combine two claims.
Premisecitation§ KRAS AND PI3K SIGNALING INHIBITORS · p. 6Many human tumors are driven by gain-of-function mutations in KRAS, PIK3CA, or BRAF, or by PTEN deletions, causing constitutive mitogenic signaling through AKT1 and MTOR or MEK.
“Several human tumors are driven by gain-of-function mutations in KRAS , PI3KCA , or B-Raf proto-oncogene, serine/threonine kinase ( BRAF ), as well as by phosphatase and tensin homolog ( PTEN ) deletions”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Hoxhaj and Manning, 2020
Not checked in the free run.
- cites Moore et al., 2020 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Cell · p. 3This cytokine secretion occurs either after endogenous retrovirus derepression and nucleic acid sensing or after permanent cell cycle blockage with a senescence-associated secretory phenotype.
“This occurs either upon the derepression of endogenous retroviruses and consequent nucleic acid sensing (Goel et al., 2017; Vanpouille-Box et al., 2019) or following the establishment of a permanent cell cycle blockage (i.e., cellular senescence) characterized by an abundant secretory component, the so-called senescence-associated secretory phenotype (SASP) (Jerby-Arnon et al., 2018).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ KRAS AND PI3K SIGNALING INHIBITORS · p. 6BRAF, PI3K, MTOR, and MEK inhibitors have become FDA-approved targeted anticancer agents, while KRAS inhibitors are not yet licensed and AKT1 inhibitors are in early development.
“while BRAF, PI3K, MTOR, and MEK inhibitors have been successfully developed into FDA-approved targeted anticancer agents, KRAS inhibitors have not yet been licensed for use in humans, and the development of AKT1 inhibitors is in its infancy”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Hoxhaj and Manning, 2020
Not checked in the free run.
- cites Moore et al., 2020 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 6Deleting Cdk8 in NK cells improves effector functions and gives robust control of syngeneic melanomas, lymphomas, and leukemias.
“deletion of Cdk8 in NK cells results in superior effector functions coupled to robust control of syngeneic melanomas, lymphomas, and leukemias (Witalisz-Siepracka et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Witalisz-Siepracka et al., 2018
Not checked in the free run.
May combine two claims.
Interpretationcitation§ CYCLIN-DEPENDENT KINASE INHIBITORS · p. 2CDK4/CDK6 inhibitors and other CDK inhibitors both halt malignant cell proliferation and produce multiple immunomodulatory effects.
“Accumulating evidence suggests that CDK4/CDK6 inhibitors, as well as inhibitors of other CDKs, do not only arrest the proliferation of malignant cells, they also mediate multipronged immunomodulatory effects (Klein et al., 2018; Petroni et al., 2020)”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ Review Cell · p. 6This enhanced antigen presentation correlates with better disease control, depletion of TREG cells and MDSCs, and added benefit from ICIs.
“correlating with (1) superior disease control in vivo , along with the systemic depletion of immunosuppressive cells including TREG cells and myeloidderived suppressor cells (MDSCs), as well as (2) added therapeutic benefits from ICIs”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Teo et al., 2017
Not checked in the free run.
- cites Whittle et al., 2020 source
Not checked in the free run.
May combine two claims. The quote only partly states this claim.
Premisecitation§ Review Cell · p. 6CDK7 inhibition in lung cancer cells promotes genomic instability linked to secretion of TH1 cytokines such as TNF, CXCL9, and CXCL10, and lowers PD-L1 via p38 and MYCN repression.
“Pharmacological inhibition of CDK7 in lung cancer cells promotes genomic instability linked to the secretion of T-helper 1 (TH1) cytokines such as tumor necrosis factor (TNF), chemokine (C-X-C motif) ligand 9 (CXCL9), and CXCL10”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Wang et al., 2020b
Not checked in the free run.
- cites Zhang et al., 2020a
Not checked in the free run.
The quote only partly states this claim.
Interpretationcitation§ Review Cell · p. 11Prebiotics that boost general immune tonus, such as inulin, can avoid or reverse the detrimental effect of MEK inhibition.
“(4) prebiotics that boost general immune tonus, such as inulin (Li et al., 2020b)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Li et al., 2020b
Not checked in the free run.
May combine two claims.
Interpretationreasoning§ KRAS AND PI3K SIGNALING INHIBITORS · p. 6Many KRAS/PI3K pathway inhibitors both limit mitogenic signaling in cancer cells and produce therapeutically relevant immunomodulatory effects.
“Interestingly, many of these agents not only limit mitogenic signaling in cancer cells but also mediate a panel of therapeutically relevant immunomodulatory effects (Table 2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Table 2
Not checked in the free run.
May combine two claims.
Premisecitation§ ll · p. 11PD-1+ melanoma cells that appear after BRAF/MEK co-inhibition have limited proliferative capacity and increased stemness features, and may be a major source of chemoresistance.
“PD-1 + melanoma cells emerging upon BRAF/MEK co-inhibition display limited proliferative potential and increased stemness features, potentially constituting the major source of chemoresistance (Sanlorenzo et al., 2018)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sanlorenzo et al., 2018 source
Not checked in the free run.
May combine two claims.
Premisecitation§ ll · p. 11In tumors treated with BRAF or MEK inhibitors, the tumor microenvironment contains more T cells that express IFNG and CD40LG, but fewer MDSCs and immunosuppressive TAMs.
“the TME of tumors treated with BRAF or MEK inhibitors is enriched in T cells expressing IFNG and the immunostimulatory receptor CD40 ligand (CD40LG) (Ho et al., 2014) but depleted of MDSCs and immunosuppressive tumor-associated macrophages (TAMs) (Allegrezza et al., 2016a; Baumann et al., 2020; Poon et al., 2017)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Ho et al., 2014
Not checked in the free run.
- cites Allegrezza et al., 2016a
Not checked in the free run.
- cites Baumann et al., 2020 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 11PTEN deletion in triple-negative breast cancer cell lines increases PD-L1 expression, which can be reversed by AKT1 or MTOR inhibition and by PI3Kα inhibition together with CDK4/CDK6 blockage.
“PTEN deletion in triple-negative breast cancer (TNBC) cell lines promotes PD-L1 upregulation, which can be reverted by AKT1 or MTOR inhibition (Mittendorf et al., 2014) as well as by PI3K a inhibition in the context of CDK4/CDK6 blockage (Teo et al., 2017)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Mittendorf et al., 2014
Not checked in the free run.
- cites Teo et al., 2017
Not checked in the free run.
May combine two claims.
Premisecitation§ ll · p. 11PD-1 or PD-L1 blockers and immunostimulatory antibodies against OX40 or 4-1BB enhance the therapeutic activity of MEK inhibition in vivo in syngeneic immunocompetent models.
“the ability of PD-1 or PD-L1 blockers (Liu et al., 2015; Loi et al., 2016) as well as immunostimulatory antibodies targeting TNF receptor superfamily member 4 (TNFRSF4, best known as OX40) or TNFRSF9 (best known as 4-1BB) (Dushyanthen et al., 2017) to improve the therapeutic activity of MEK inhibition in vivo , in syngeneic immunocompetent settings”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ ll · p. 11Vemurafenib lowers the surface expression of several NK-cell-activating ligands on malignant cells, which mediates immunosuppressive effects.
“vemurafenib downregulates the expression of various NK-cell-activating ligands (NKALs) on the surface of malignant cells, hence mediating immunosuppressive effects (Lo ´ pez-Cobo et al., 2018)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lo ´ pez-Cobo et al., 2018
Not checked in the free run.
May combine two claims.
Premisecitation§ ll · p. 11MEK signaling is important for expanding naive T cells during priming and for protecting tumor-infiltrating CD8+ CTLs from death caused by chronic TCR stimulation.
“this reflects the key role of MEK signaling in the expansion of naive T cells at priming, as well as in the protection of tumor-infiltrating CD8 + CTLs from the lethal consequences of chronic TCR stimulation (Boni et al., 2010; Ebert et al., 2016)”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ DDR- AND APOPTOSIS-TARGETING AGENTS · p. 12Many human neoplasms arise in the context of genetic defects that impair DNA damage repair in premalignant or malignant cells or prevent apoptosis of cells with DNA damage.
“Multiple human neoplasms emerge in the context of (epi)genetic defects that limit the ability of (pre)malignant cells to repair DNA damage, such as loss-of-function mutations in BRCA1 DNA repair associated ( BRCA1 ), or prevent the apoptotic demise of cells accumulating DNA damage, such as alterations in the tumor protein p53 (TP53, best known as p53) system (Pilie ´ et al., 2019) or upregulation”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ ll · p. 12In some settings, PARP inhibitor-induced type I IFN is accompanied by release of T-cell chemoattractants including CXCL10 and by paracrine STING activation in DCs, leading to upregulation of MHC class II molecules and co-stimulatory ligands that support T-cell priming.
“In some settings, this was accompanied by the release of T-cell chemoattractants, including CXCL10, as well as by paracrine STING activation in DCs, ultimately leading to upregulation of MHC class II molecules and co-stimulatory ligands in support of T-cell priming (Ding et al., 2018; Pantelidou et al., 2019)”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DDR- AND APOPTOSIS-TARGETING AGENTS · p. 12The BCL2 inhibitor venetoclax is approved by regulatory agencies for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.
“the BCL2 inhibitor venetoclax has been approved by regulatory agencies for use in patients with CLL or small lymphocytic lymphoma (SLL) (Ashkenazi et al., 2017)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ashkenazi et al., 2017 source
Not checked in the free run.
May combine two claims.
Interpretationreasoning§ Review Cell · p. 12Deregulated KRAS and PI3K signaling has strong oncogenic effects while also favoring immune evasion.
“deregulated KRAS and PI3K signaling mediates robust oncogenic effects while favoring immunoevasion”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ Review Cell · p. 11Pharmacological or genetic inhibition of PI3Kα, PI3Kδ, or AKT boosts effector T cell survival and activation by promoting autocrine IL2 signaling or by reducing the intratumoral abundance or suppressive functions of TREG cells, MDSCs, and TAMs.
“Pharmacological or genetic inhibition of PI3K a , PI3K d , or AKT has been proposed to boost TEFF cell survival and activation by promoting autocrine IL2 signaling (Aragoneses-Fenoll et al., 2018; Carnevalli et al., 2018), or by limiting the intratumoral abundance or suppressive functions of TREG cells (Abu-Eid et al., 2014; Ali et al., 2014; Chellappa et al., 2019; Lim et al., 2018), MDSCs (Davis”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Aragoneses-Fenoll et al., 2018
Not checked in the free run.
- cites Carnevalli et al., 2018
Not checked in the free run.
- cites Abu-Eid et al., 2014
Not checked in the free run.
May combine two claims.
Interpretationcitation§ Review Cell · p. 12Autophagy activation by MTOR inhibitors produces immunomodulatory effects that are highly context-dependent, which complicates the development of pharmacological autophagy modulators for cancer therapy.
“autophagy activation by MTOR inhibitors mediates immunomodulatory effects with an elevated degree of context dependency, complicating the development of pharmacological autophagy modulators for cancer therapy (Galluzzi et al., 2017a)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Galluzzi et al., 2017a
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 16The immunosuppressive effects of RT-induced G2/M blockage can be offset by p53 loss or CHEK1 inhibition, leading to micronuclei accumulation, stronger type I IFN signaling, and potent systemic anticancer immunity.
“Interestingly, the immunosuppressive effects of RT-driven G2/ M cell cycle blockage can also be offset by genetic (loss of the mouse p53-coding gene) and pharmacological (CHEK1 inhibition) interference with the G1 checkpoint, ultimately resulting in accrued accumulation of micronuclei, superior type I IFN signaling, and initiation of potent anticancer immunity with systemic outreach (Chen et al.,”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chen et al., 2020 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 16ATM drives IL8 secretion by breast cancer cells independently of its DNA damage response role, promoting disease progression through autocrine or paracrine mechanisms.
“similar lines, ATM reportedly drives IL8 secretion by breast cancer cells independently of its role in the DDR, ultimately favoring disease progression via autocrine or paracrine mechanisms (Chen et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chen et al., 2015 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 16Venetoclax eliminates HR+ breast cancer cells that become senescent after CDK4/CDK6 inhibition, increasing MHC class I and PD-L1 levels.
“In line with such a ''senolytic'' activity, venetoclax effectively eliminates HR + breast cancer cells undergoing senescence in response to CDK4/CDK6 inhibitors, culminating in increased levels of both MHC class I molecules and PD-L1 (Whittle et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Whittle et al., 2020 source
Not checked in the free run.
May combine two claims.
Premisecitation§ ll · p. 16Nutlin 3a-induced p53 reactivation elicits ICD in B16 melanomas, correlating with DC activation, CD8+ CTL expansion, and MDSC depletion.
“Accordingly, p53 reactivation by nutlin 3a, a pharmacological inhibitor of the p53-degrading enzyme MDM2 proto-oncogene (MDM2), elicits ICD in B16 melanomas, correlating with DC activation, expansion of tumor-infiltrating CD8 + CTLs, and depletion of immunosuppressive MDSCs (Guo et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Guo et al., 2017 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 16Venetoclax and navitoclax are especially toxic to senescent cells, which in some settings produce immunomodulatory cytokines such as IL6 and VEGFA.
“Venetoclax and navitoclax (an experimental inhibitor of various BCL2 family members) are particularly toxic for senescent cells, which (at least in some settings) produce immunomodulatory cytokines, including IL6 and VEGFA (Gorgoulis et al., 2019).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gorgoulis et al., 2019 source
Not checked in the free run.
May combine two claims.
Premisecitation§ ll · p. 16ABT-737 increases MDSC sensitivity to FAS-driven apoptosis in vitro and suppresses MDSC accumulation in murine mammary carcinomas.
“Moreover, ABT-737 increases the sensitivity of MDSCs to FAS-driven apoptosis in vitro and suppresses MDSC accumulation in murine mammary carcinomas (Hu et al., 2013), even though its administration has been related to depletion of TEFF cells and enrichment of TREG cells in tumorfree mice (Gabriel et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hu et al., 2013
Not checked in the free run.
May combine two claims.
Premisecitation§ ll · p. 16Increased infiltration by exhausted PD-1+ CD8+ CTLs is associated with relapse of MYCN-driven mammary carcinomas after withdrawal of BCL2/BCL-XL inhibitors, and this relapse can be treated with PD-1 blockers.
“Interestingly, increased tumor infiltration by exhausted PD-1 + CD8 + CTLs has been associated with the relapse of MYCN-driven mammary carcinomas upon withdrawal of BCL2/BCL-XL inhibitors, which also appears to be therapeutically actionable with PD-1 blockers (Haikala et al., 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Haikala et al., 2019
Not checked in the free run.
May combine two claims.
Premisecitation§ ll · p. 16Venetoclax does not impair TEFF responsiveness to antigenic stimuli in vitro; it upregulates BCL-XL and supports T-cell survival, synergizing with ICIs in immunocompetent mouse colorectal carcinoma models.
“Along similar lines, BCL2 inhibition by venetoclax does not impair TEFF cell responsiveness to antigenic stimuli in vitro , but rather promotes the compensatory upregulation of BCL2-like 1 (BCL2L1, best known as BCL-XL) and hence supports T-cell survival, de facto synergizing with ICIs in immunocompetent mouse models of colorectal carcinoma (Kohlhapp et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kohlhapp et al., 2020
Not checked in the free run.
May combine two claims.
Premisecitation§ ll · p. 16p53 is genetically or functionally lost in many malignancies, and this loss correlates with signs of local immunosuppression.
“One of the main actors in DDR-driven BCL2-inhibitable apoptosis, p53, is genetically or functionally lost in a variety of malignancies (Pilie ´ et al., 2019), correlating with signs of local immunosuppression (Cui and Guo, 2016).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Pilie ´ et al., 2019 source
Not checked in the free run.
- cites Cui and Guo, 2016
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 16Co-inhibition of ATM and WEE1 in human KRAS G12C-driven PDAC cells lowers secretion of IL8 and other invasion-supporting factors and reduces PD-L1 expression.
“Accordingly, co-inhibition of ATM and WEE1 G2 checkpoint kinase (WEE1, another component of the DDR machinery) in human KRAS G12C -driven pancreatic ductal adenocarcinoma cancer (PDAC) cells results in decreased secretion of IL8 and other factors supporting local invasion, as well as in reduced PD-L1 expression (Jin et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jin et al., 2020
Not checked in the free run.
May combine two claims.
Premisecitation§ ll · p. 16Pharmacological p53 reactivation establishes cellular senescence linked to an immunostimulatory SASP that recruits and activates NK cells, TEFF cells, and tumoricidal macrophages.
“Additional immunostimulatory effects linked to pharmacological p53 reactivation in cancer cells include (but are not limited to) (1) downregulation of immunomodulatory cytokines linked to tumor progression, such as IL6 (Sahin et al., 2020); (2) upregulation of NKALs (Textor et al., 2011); and (3) establishment of cellular senescence linked to an immunostimulatory SASP that favors the recruitment”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ HER2, EGFR, VEGFA, AND TGFb INHIBITORS · p. 17The therapeutic activity of HER2-targeting mAbs correlates with NK cell abundance, is influenced by FcγR polymorphisms, and can be boosted preclinically by preventing NK dysfunction.
“Accordingly, the therapeutic activity of these mAbs correlates with the abundance of NK cells, is influenced by genetic polymorphisms affecting Fc g R functions, and can be boosted (at least preclinically) by immunotherapeutic interventions preventing NK dysfunction (e.g., IL2 or IL12 administration) (Gennari et al., 2004; Jaime-Ramirez et al., 2011; Klein et al., 2017; Kono et al., 2002; Musolino”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ ll · p. 16Alisertib depletes MDSCs in mouse mammary tumors and mediates an immunotherapeutic effect that ICIs can enhance.
“Consistent with this notion, the AURKA inhibitor alisertib appears to promote tumor infiltration of CD8 + T cells via a non-canonical pathway involving IL10 secretion (Han et al., 2020b) and to directly deplete the MDSC compartment of mouse mammary tumors, ultimately mediating an immunotherapeutic effect that can be enhanced by ICIs (Yin et al., 2019).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yin et al., 2019 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 17EGFR-specific mAbs and EGFR-targeting TKIs such as erlotinib, when given with a tumor-targeting mAb, promote NK-cell ADCC; for TKIs this arises from upregulation of the mAb target on malignant cells.
“Not only EGFR-specific mAbs (Roberti et al., 2011) but also EGFR-targeting TKIs such as erlotinib (in the presence of a tumor-targeting mAb) (Cavazzoni et al., 2012; Mallmann-Gottschalk et al., 2019) promote ADCC by NK cells, which, in the case of TKIs, originates from the upregulation of the mAb target (e.g., EGFR, HER2) by malignant cells (Cavazzoni et al., 2012; Mallmann-Gottschalk et al., 2019”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ Review Cell · p. 17EGFR-targeted agents induce ICD and consequent calreticulin exposure coupled with CD47 downregulation on malignant cells.
“At least in part, this reflects the ability of EGFR-targeted agents to induce ICD (Garrido et al., 2011; Pozzi et al., 2016) (Box 1) and the consequent exposure of the ''eat-me'' signal calreticulin (CALR) coupled to the downregulation of the ''don't eat me'' signal CD47 on the surface of malignant cells (Nigro et al., 2019).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ Review Cell · p. 17Combining HER2-specific mAbs with pan-PI3K inhibitors or EGFR-specific mAbs produces therapeutic benefit linked to immune activation in preclinical tumor models.
“A similar therapeutic benefit linked to signs of immune activation has also been documented (in preclinical tumor models) upon combining HER2specific mAbs with other targeted anticancer agents that mediate immunomodulatory properties, including pan-PI3K inhibitors (Choi et al., 2018) and EGFR-specific mAbs (Roda et al., 2007).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Choi et al., 2018
Not checked in the free run.
- cites Roda et al., 2007
Not checked in the free run.
May combine two claims.
Premisecitation§ HER2, EGFR, VEGFA, AND TGFb INHIBITORS · p. 17ERBB2 amplification and gain-of-function EGFR mutations support proliferation of various cancer cell types.
“Indeed, while ERBB2 gene amplifications and gain-of-function EGFR mutations support the proliferation of various cancer cell types (Oh and Bang, 2020; Pao and Chmielecki, 2010), VEGFA is critical for tumor-driven neoangiogenesis (Apte et al., 2019) and TGFb promotes the establishment of a fibrotic microenvironment that is poorly permissive to access by therapeutics (Derynck et al., 2020).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Oh and Bang, 2020
Not checked in the free run.
- cites Pao and Chmielecki, 2010 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 17This T-cell response reflects improved antigen presentation on MHC class I and II molecules and MYD88-dependent immunostimulation, increasing antigen processing and presentation by DCs.
“tation on MHC class I and II molecules (Kono et al., 2004; Triulzi et al., 2018), as well as MYD88 innate immune signal transduction adaptor (MYD88)-dependent immunostimulation (Stagg et al., 2011), culminating in increased antigen processing and presentation by DCs (Gall et al., 2017).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ Review Cell · p. 17Various EGFR-targeting agents improve MHC class I antigen presentation by cancer cells and favor tumor material uptake by DCs, T-cell priming, and NK-cell activation without additional immunostimulatory signals.
“In addition, various EGFRtargeting agents improve MHC class I antigen presentation by cancer cells (Lizotte et al., 2018; Pollack et al., 2011) and favor the uptake of tumor material by DCs (Banerjee et al., 2008; Nigro et al., 2019) as well as their ability to prime T cells and promote NK-cell activation in the absence of additional immunostimulatory signals (Banerjee et al., 2008; Lee et al., 2”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ Review Cell · p. 17ADCP-associated M2 polarization relies on AIM2 sensing of DNA from phagocytosed tumor cells, causing CGAS cleavage and inflammasome-dependent PD-L1 and IDO1 upregulation.
“This process appears to rely on the sensing of DNA from phagocytosed tumor cells by absent in melanoma 2 (AIM2), resulting in CGAS cleavage coupled to PD-L1 and IDO1 upregulation via an inflammasome-dependent mechanism (Su et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Su et al., 2018
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 17Multiple immunotherapeutic agents, including DC vaccines, TLR2 agonists, IL21, and PD-L1 blockers, can magnify the efficacy of HER2-targeting mAbs and elicit robust anticancer immunity.
“In line with this notion, the progressive loss of HER2-targeting CD4 + TH1 cells reportedly facilitates HER2-driven mammary carcinogenesis (Datta et al., 2015a), and multiple immunotherapeutic agents, including DC-based vaccines (Datta et al., 2015b; Linch et al., 2016), TLR2 agonists (Lu et al., 2011), recombinant IL21 (Roda et al., 2006), and PD-L1 blockers (Mittal et al., 2019), can be”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Datta et al., 2015b
Not checked in the free run.
- cites Linch et al., 2016
Not checked in the free run.
- cites Lu et al., 2011
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 18Gefitinib upregulates NKALs in NSCLC cells, linked to enhanced NK-mediated ADCC.
“NKAL upregulation by NSCLC cells, linked to enhanced NK-mediated ADCC”
Quote in the paperSubstantial claim0 of 2 sources checked- cites He et al., 2013
Not checked in the free run.
- cites Kim et al., 2011 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 19EGFR-targeting agents such as gefitinib and osimertinib cause temporary accumulation of DCs and CD8+ TEFF cells with TREG and M2 TAM depletion in NSCLC, followed by MDSC-driven immunosuppression.
“temporary DC and CD8 + T EFF accumulation coupled to T REG cell and M2TAMdepletion, rapidly followed by MDSC-driven immunosuppression in vivo”
- Also stated in: § Review Cell · p. 19 · hedged
“the TME of NSCLC exposed to EGFR-targeting agents exhibits increased abundance of DCs and CD8 + TEFF cells exhibiting limited signs of exhaustion coupled to the depletion of TREG cells and M2 TAMs, although such an effect appeared to be temporary and rapidly followed by MDSC-driven immunosuppression”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jia et al., 2019 source
Not checked in the free run.
- Also stated in: § Review Cell · p. 19 · hedged
May combine two claims.
Premisecitation§ Review Cell · p. 18Gefitinib downregulates PD-L1 in NSCLC cells bearing EGFR mutations in vitro and in vivo, relieving immunosuppression.
“PD-L1 downregulation in NSCLC cells bearing EGFR mutations in vitro and in vivo”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ Review Cell · p. 19Anti-TGFb1,2 IgG2a upregulates MHC class I in squamous cell carcinoma cells, improving antigen presentation.
“MHCclass I upregulation by squamous cell carcinoma cells”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tauriello et al., 2018 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 18Afatinib, erlotinib, and gefitinib upregulate MHC class I and II in ovarian carcinoma cells, improving antigen presentation by cancer cells.
“MHC class I and II upregulation by ovarian carcinoma cells”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lizotte et al., 2018 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 187A7 mAb induces ICD in lung cancer cells, with DAMP emission linked to DC maturation in vitro.
“DAMPemission by lung cancer cells, linked to DC maturation in vitro”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Garrido et al., 2011 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 18Cetuximab activates DCs by enhancing uptake of tumor material and cross-presentation, followed by T-cell priming and NK-cell activation.
“enhanced uptake of tumor material and cross-presentation by DCs, followed by priming of T cells and activation of NK cells”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ Review Cell · p. 19Trastuzumab and pertuzumab activate NK cells and induce NK-cell-mediated ADCC of HER2-expressing cancer cells.
“induction of NK-cell-mediated ADCC of HER2-expressing cancer cells”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Misumi et al., 2018 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 19Trastuzumab upregulates MHC class I and II in HER2-overexpressing cancer cells and HER2+ breast cancer biopsies, improving antigen presentation.
“MHC class I and II upregulation in different HER2-overexpressing cancer cells and HER2 + BC biopsies”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ Review Cell · p. 18Cetuximab activates NK cells and induces NK-cell-mediated ADCC of cancer cells with mutated KRAS.
“induction of NK-cell-mediated ADCC of cancer cells with mutated KRAS”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Roberti et al., 2011 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 18Cetuximab induces ICD in rectal carcinoma cells, with DAMP emission enhanced by chemotherapy and linked to phagocytosis of tumor cells by DCs.
“DAMP emission by rectal carcinoma cells, enhanced by chemotherapy and linked to phagocytosis of tumor cells by DCs”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pozzi et al., 2016 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 18Erlotinib activates NK cells and induces NK-cell-mediated ADCC of ovarian cancer and NSCLC cells.
“induction of NK-cell-mediated ADCC of ovarian cancer and NSCLC cells”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ Review Cell · p. 19Trastuzumab activates macrophages and induces ADCP of HER2-expressing cancer cells.
“induction of ADCP of HER2-expressing cancer cells”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shi et al., 2015 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 18Cetuximab polarizes M2-like TAMs that express high PD-L1 and secrete IL10 and VEGFA, as seen upon ADCP in vitro.
“PD-L1 upregulation in macrophages upon ADCP in vitro”
- Also stated in: § Review Cell · p. 19 · hedged
“coupled to the accumulation of immunosuppressive M2-like TAMs expressing high PD-L1 levels and secreting IL10 and VEGFA”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pander et al., 2011 source
Not checked in the free run.
- Also stated in: § Review Cell · p. 19 · hedged
The quote only partly states this claim.
Premisecitation§ Review Cell · p. 19Apatinib and sunitinib downregulate PD-L1 in osteosarcoma cells upon STAT3 inactivation, relieving immunosuppression.
“PD-L1 downregulation in osteosarcoma cells upon inactivation of STAT3”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Duan et al., 2020 source
Not checked in the free run.
- cites Zheng et al., 2018
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 18IgA2 EGFR antibody activates macrophages and induces ADCP of epidermal carcinoma cells in vivo.
“induction of ADCP of epidermal carcinoma cells in vivo”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Boross et al., 2013
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Review Cell · p. 18PD168393 upregulates MHC class I in primary and malignant human keratinocytes.
“MHC class I upregulation in primary and malignant human keratinocytes”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Pollack et al., 2011
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 19Trastuzumab activates DCs by enhancing uptake and cross-presentation of HER2, followed by T-cell priming.
“enhanced uptake and cross-presentation of HER2 by DCs followed by T-cell priming”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gall et al., 2017
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 18Cetuximab upregulates MHC class I in primary and malignant human keratinocytes, improving antigen presentation by cancer cells.
“MHC class I upregulation in primary and malignant human keratinocytes”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pollack et al., 2011
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 19Trastuzumab polarizes M2-like TAMs, which upregulate PD-L1 and IDO1 upon ADCP, linked to improved sensitivity to ICIs in mouse HER2+ breast cancer models.
“PD-L1 and IDO1 upregulation by TAMs upon ADCP, linked to improved sensitivity to ICIs in mouse models of HER2 + BC”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Su et al., 2018
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 18Gefitinib downregulates NKALs in NSCLC cells, linked to reduced NK-mediated ADCC.
“NKAL downregulation in NSCLC cells, linked to reduced NK-mediated ADCC”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Okita et al., 2015 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 18Erlotinib upregulates MHC class II in DCs and macrophages, improving antigen presentation by immune cells.
“MHC class II upregulation by DCs and macrophages”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Venugopalan et al., 2016 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 19Galunisertib upregulates MHC class I in hepatic tumor organoids, linked to boosted TEFF responses and improved sensitivity to ICIs in vivo.
“MHC class I upregulation by hepatic tumor organoid, linked to boosted T EFF cell responses and improved sensitivity to ICIs in vivo”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dodagatta-Marri et al., 2019
Not checked in the free run.
May combine two claims. The quote only partly states this claim.
Premisecitation§ Review Cell · p. 19A2V promotes vascular remodeling and TEFF cell extravasation via adhesion molecules and pro-inflammatory cytokines by ECs in mammary tumors.
“T EFF cell extravasation upon expression of adhesion molecules and pro-inflammatory cytokines by ECs in mammary tumors”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schmittnaegel et al., 2017 source
Not checked in the free run.
May combine two claims. The quote only partly states this claim.
Premisecitation§ Review Cell · p. 19Bevacizumab downregulates PD-L1 in biopsies from glioblastoma patients, relieving immunosuppression.
“PD-L1 downregulation in biopsies from patients with glioblastoma”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tamura et al., 2019
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 19A2V upregulates PD-L1 in cancer and ECs of mammary tumors, linked to improved sensitivity to ICIs in vivo.
“PD-L1 upregulation in cancer and ECs of mammary tumors, linked to improved sensitivity to ICIs in vivo”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Schmittnaegel et al., 2017 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 20VEGFR2 inhibition with apatinib reverses immunosuppression and sensitizes VEGFA-overexpressing mammary and colorectal mouse tumors to PD-1 blockade.
“kinase insert domain receptor (KDR, best known as VEGFR2) inhibition with apatinib reverses immunosuppression and sensitizes VEGFA-overexpressing mammary and colorectal mouse tumors to immunotherapy with PD-1 blockers”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wang et al., 2020c
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 20Similar immunomodulatory findings have been documented in blood or tumor samples from renal cell carcinoma patients receiving sunitinib and NSCLC or mammary carcinoma patients receiving bevacizumab.
“Similar findings have been documented in blood or tumor samples from patients with renal cell carcinoma receiving sunitinib”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation§ Review Cell · p. 19The discrepancy in gefitinib effects on NKALs may reflect a cell-type-dependent mechanism linked to EGFR mutational status and/or drug concentration.
“potentially reflecting a cell-type-dependent mechanism linked to EGFR mutational status and/or the concentration of the drug employed in this context”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Okita et al., 2015 source
Not checked in the free run.
May combine two claims.
Interpretationcitation§ Review Cell · p. 21Clinical responses in that study were limited, most likely due to PD-1-dependent functional defects of the T-cell compartment at baseline.
“clinical responses in this study were limited, most likely as a consequence of PD-1-dependent functional defects of the T-cell compartment at baseline”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Formenti et al., 2019 source
Not checked in the free run.
May combine two claims. The quote only partly states this claim.
Premisecitation§ Review Cell · p. 21Pharmacological inhibition of TGFb or its receptors resolves immunological exclusion and improves antigen presentation by malignant cells, leading to potent anticancer immune responses with ICIs toward disease eradication and protective immunological memory in mouse models of melanoma, colorectal, breast, and squamous cell carcinoma.
“pharmacological inhibition of TGFb or its receptors resolves immunological exclusion and improves antigen presentation by malignant cells, culminating in potent anticancer immune responses that can be actioned with ICIs toward disease eradication and establishment of protective immunological memory, at least in mouse models of melanoma”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ Review Cell · p. 21TGFb favors expansion of TREG cells and MDSCs, culminating in local and systemic immunosuppression.
“favor the expansion of TREG cells and MDSCs, culminating in local and systemic immunosuppression”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Batlle and Massague, 2019
Not checked in the free run.
May combine two claims.
Premisecitation§ OTHERS · p. 21Imatinib demonstrates immunostimulatory effects linked to NK-cell activation and TREG cell depletion.
“Imatinib was arguably the first targeted anticancer agent to demonstrate immunostimulatory effects that are directly linked to NK-cell activation”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ Review Cell · p. 22In preclinical non-small cell lung cancer models, crizotinib treatment is linked to higher T-cell exhaustion markers and increased PD-L1 on cancer cells.
“The multi-TKI crizotinib has also been associated with increased markers of T-cell exhaustion and PD-L1 upregulation on malignant cells in preclinical NSCLC models”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liu et al., 2019 source
Not checked in the free run.
Classified as probably not a substantial claim.
Interpretationreasoning§ Review Cell · p. 21Combinatorial regimens involving ICIs and other immunomodulatory drugs offer added therapeutic possibilities.
“with emphasis on the added therapeutic possibilities offered by combinatorial regimens involving ICIs and other immunomodulatory drugs”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ Review Cell · p. 22Imatinib treatment is associated with PD-1 upregulation in T cells from GIST patients and PD-L1 downregulation on mouse GIST cells, correlating with added therapeutic effect of PD-1 blockade with imatinib in a preclinical GIST model.
“imatinib treatment has been associated with PD-1 upregulation in T cells from patients with GIST (but with PD-L1 downregulation on mouse GIST cells), correlating with an added therapeutic effect for PD-1 blockage in the context of imatinib administration in a preclinical GIST model”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Seifert et al., 2017 source
Not checked in the free run.
May combine two claims.
Premisecitation§ OTHERS · p. 21Imatinib clinical activity in GIST is linked to IFNG production by patient NK cells and NK-cell-activating receptor expression pattern.
“the clinical activity of imatinib in individuals with GIST is linked to IFNG production by the patient's NK cells”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Menard et al., 2009 source
Not checked in the free run.
- cites Delahaye et al., 2011
Not checked in the free run.
- cites Rusakiewicz et al., 2017
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 22EZH2 inhibition reprograms TREG cells and creates a tumor microenvironment that permits anticancer immunity.
“TREG reprogramming coupled to the establishment of a TME permissive for anticancer immunity”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Sun et al., 2020
Not checked in the free run.
- cites Wang et al., 2018
Not checked in the free run.
- cites Zingg et al., 2017
Not checked in the free run.
May combine two claims.
Premisecitation§ OTHERS · p. 21CML patients achieving deep molecular responses on imatinib or other TKIs exhibit restored NK-cell activity, PD-1 downregulation on T cells, and contraction of the MDSC compartment.
“patients with CML achieving deep molecular responses upon treatment with imatinib or other TKIs”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hughes et al., 2017
Not checked in the free run.
May combine two claims.
Premisecitation§ OTHERS · p. 21Imatinib and nilotinib enable M2-like TAMs to repolarize toward an M1-like phenotype and activate NK cells in response to TLR stimulation.
“both imatinib and nilotinib enable M2like TAMs to repolarize toward an M1-like phenotype and activate NK cells in response to TLR stimulation”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Bellora et al., 2017
Not checked in the free run.
- cites Zhang et al., 2018b
Not checked in the free run.
May combine two claims.
Premisecitation§ OTHERS · p. 21CLL patients treated with ibrutinib show reversal of T-cell exhaustion and diversification of the circulating TCR repertoire.
“A similar reversal of T-cell exhaustion coupled to a diversification of the circulating TCR repertoire has been observed in patients with CLL treated with the BTK inhibitor ibrutinib”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Kondo et al., 2018
Not checked in the free run.
- cites Yin et al., 2017
Not checked in the free run.
May combine two claims.
Premisecitation§ Review Cell · p. 25TREG cells express CDK4/CDK6 and VEGF receptors, making them especially sensitive to CDK4/CDK6 inhibitors and bevacizumab.
“TREG cells express CDK4/CDK6 as well as VEGF receptors (Goel et al., 2017; Terme et al., 2013) and hence are particularly sensitive to CDK4/CDK6 inhibitors and bevacizumab”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Interpretationreasoning§ ll · p. 22Most, if not all, targeted anticancer agents exert immunomodulatory effects that matter for therapeutic efficacy and for designing better combinatorial regimens.
“Taken together, these observations lend additional support to the notion that most, if not all, targeted anticancer agents mediate immunomodulatory effects that are highly relevant not only for therapeutic efficacy but also for the design of novel combinatorial regimens with superior clinical impact.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Box 2. ICIs for cancer therapy · p. 26Several immune checkpoint inhibitors targeting other co-inhibitory receptors are being extensively tested in clinical trials.
“various ICIs targeting other co-inhibitory receptors are being extensively tested for efficacy in clinical trials”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Interpretationnone given§ CONCLUDING REMARKS · p. 22Targeted anticancer agents produce strong immunomodulatory effects that can influence their clinical activity.
“Targeted anticancer agents mediate robust immunomodulatory effects that may influence their clinical activity”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Box 2. ICIs for cancer therapy · p. 26Approved immune checkpoint inhibitors include CTLA4 blockers such as ipilimumab, PD-1 inhibitors such as pembrolizumab, nivolumab, and cemiplimab, and PD-L1 inhibitors such as avelumab, atezolizumab, and durvalumab.
“These agents include blockers of cytotoxic T lymphocyte-associated protein 4 (CTLA4), such as ipilimumab, as well as inhibitors of programmed cell death 1 (PDCD1, best known as PD-1), such as pembrolizumab, nivolumab, and cemiplimab, or its main ligand CD274 (best known as PD-L1), such as avelumab, atezolizumab, and durvalumab”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ribas and Wolchok, 2018
Not checked in the free run.
May combine two claims.
Premisecitation§ Box 2. ICIs for cancer therapy · p. 26Experimental immune checkpoint inhibitors include agents against LAG3, VISTA, TIM-3, and NKG2A.
“inhibitors of lymphocyte activating 3 (LAG3), V-set immunoregulatory receptor (VSIR, best known as VISTA), and hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM-3), as well as drugs that block the NK-cell co-inhibitory receptor killer cell lectin-like receptor C1 (KLRC1, best known as NKG2A)”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ Review Cell · p. 25Abemaciclib, although designed to inhibit CDK4/CDK6, also targets other CDKs and CDK-unrelated kinases.
“abemaciclib was conceived to inhibit CDK4/CDK6 but has been shown to target other CDKs as well as CDK-unrelated kinases”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chen et al., 2016 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Box 2. ICIs for cancer therapy · p. 26Monoclonal antibodies that block co-inhibitory receptors on immune effector cells or their ligands on neoplastic and myeloid cells produce strong immunostimulation that can reactivate anticancer immune responses and yield clinical benefit in many malignancies.
“monoclonal antibodies that block co-inhibitory receptors (on immune effector cells) or their ligands (on neoplastic and myeloid cells) mediate immunostimulatory effects so robust as to translate in the (re)activation of anticancer immuneresponses associated with clinical benefits in patients affected by an ever-growing number of malignancies”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ribas and Wolchok, 2018
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Premisenone given§ Review Cell · p. 25No targeted anticancer agent was designed specifically to produce immunomodulatory effects.
“No targeted anticancer agent was purposely designed to mediate immunomodulatory effects”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationcitation§ Review Cell · p. 25Immunomodulation by targeted anticancer therapy sometimes clearly comes from on-target effects, but often comes from alternative, frequently uncharacterized, molecular players.
“although in some cases immunomodulation by targeted anticancer therapy clearly originates from on-target effects, in many others it stems from alternative (often uncharacterized) molecular players”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Box 2. ICIs for cancer therapy · p. 26At least seven immune checkpoint inhibitors are approved by the FDA or equivalent agencies worldwide for cancer patients, covering a large range of oncological indications.
“no less than seven different immune checkpoint inhibitors (ICIs) are currently approved by the FDA or equivalent agencies worldwide for use in cancer patients, cumulatively encompassing a large panel of oncological indications”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ribas and Wolchok, 2018
Not checked in the free run.
May combine two claims.
Premisenone given§ Cell · p. 27Pharmacological inhibition of EZH2 has therapeutic activity tied to robust immunostimulation but appears linked to expansion of myeloid-derived suppressor cells.
“Pharmacological inhibition of enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) exerts therapeutic activity linked to robust immunostimulation, but appears to be associated with myeloid-derived suppressor cell (MDSC) expansion.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Premisenone given§ Cell · p. 275-fluorouracil- or gemcitabine-based chemotherapy depletes myeloid-derived suppressor cells and/or limits their immunosuppressive functions.
“chemotherapeutic regimens that deplete MDSCs and/or limit their immunosuppressive functions, such as 5-fluorouracil (5-FU)- or gemcitabine-based chemotherapy”
Quote in the paperNot a substantial claimMay combine two claims.
Premisenone given§ Cell · p. 27CDK4/CDK6 inhibitors cause robust cytostatic activity along with multipronged immunostimulatory effects and upregulation of PD-L1.
“Cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitors mediate robust cytostatic activity that is accompanied by multipronged immunostimulatory effects but also PD-L1 upregulation.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ Box 2. ICIs for cancer therapy · p. 26These findings confirm that immune effectors play a key role in the therapeutic efficacy of radiotherapy and TGFb blockers.
“Besides confirming the key role of immune effector in the therapeutic efficacy of RT and TGFb blockers”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning§ Review Cell · p. 25Experimental variables such as drug concentration, medium composition, and timing may have unexpected effects on biological outcomes.
“experimental variables such as drug concentration, precise medium composition, and time may have unsuspected effects on biological outcomes”
Quote in the paperNot a substantial claim
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Stable or transient inhibition of autophagy can limit antitumor immune responses mediated by chemotherapy, radiation therapy, and/or targeted therapy.
“as stable or transient inhibition of autophagy not only can limit antitumor immune responses mediated by chemotherapy, radiation therapy (Galluzzi et al, 2017b; Galluzzi et al, 2020a), and/or targeted therapy (Petroni et al, 2021)”
From Autophagy in major human diseases (2021) · cites this paper as Petroni et al, 2021
The citation lists haven’t been fetched yet
References 306 · Cited by 212
Research works printed but not linked: 1
- Derynck, 2020, TGFbeta biology in cancer progression and immunotherapy, Nat. Rev. Clin. Oncol.
- Authors
- Petroni, G., Buqué, A., Zitvogel, L., Kroemer, G., & Galluzzi, L.
- Affiliations
- Weill Cornell Medicine (US)
- Inserm (FR)
- Karolinska University Hospital (SE)
- Université Paris Cité (FR)
- Corresponding author
- Kroemer, Guido
- Galluzzi, Lorenzo
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 39
- Issue
- 3
- Pages
- 310-345
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W3111468108
- Semantic Scholar
- 75e8749a1c87391ba4f5748a4e8d769e40bef89c
- Cited by
- 212
- References
- 306
- Citations by year
- 2026: 8 · 2025: 27 · 2024: 44 · 2023: 50 · 2022: 47 · 2021: 36
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion, cc-by)
- Funders
- Seerave Foundation
- High-end Foreign Experts Recruitment Plan of China (GDW20171100085, GDW20181100051)
- U.S. Department of Defense (BC180476P1, ZP-6177)
- Weill Cornell Medicine
- Labex Immuno-Oncology
- Bristol-Myers Squibb
- Bayer HealthCare
- AstraZeneca
- Institut National Du Cancer
- Boehringer Ingelheim
- Cancéropôle Ile de France
- Stand Up To Cancer
- Chancellerie des Universités de Paris
- Leukemia and Lymphoma Society
- Ligue Contre le Cancer
- Weill Cornell Medical College
- Institut Universitaire de France
- Association pour la Recherche sur le Cancer
- Institut Mérieux
- Agence Nationale de la Recherche
- Genentech
- Fondation Leducq
- Roche
- Fondation pour la Recherche Médicale
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- targeted anticancer agents, immunomodulation, immunostimulatory effects, immunosuppressive activity, tumor immunology, targeted therapy, cancer immunotherapy, treatment efficacy
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Neoplasms, Disease Progression, Immunomodulation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
