Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance
Open accessAbstract
Immune checkpoint inhibitors (ICIs) have made an indelible mark in the field of cancer immunotherapy. Starting with the approval of anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) for advanced-stage melanoma in 2011, ICIs—which now also include antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1)—quickly gained US Food and Drug Administration approval for the treatment of a wide array of cancer types, demonstrating unprecedented extension of patient survival. However, despite the success of ICIs, resistance to these agents restricts the number of patients able to achieve durable responses, and immune-related adverse events complicate treatment. Thus, a better understanding of the requirements for an effective and safe antitumor immune response following ICI therapy is needed. Studies of both tumoral and systemic changes in the immune system following ICI therapy have yielded insight into the basis for both efficacy and resistance. Ultimately, by building on these insights, researchers should be able to combine ICIs with other agents, or design new immunotherapies, to achieve broader and more durable efficacy as well as greater safety. Here, we review the history and clinical utility of ICIs, the mechanisms of resistance to therapy, and local and systemic immune cell changes associated with outcome.
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- Premisecitation
In a phase I trial of advanced ipilimumab-refractory melanoma, 26% of pembrolizumab-treated patients had complete or partial response.
“In a phase I clinical trial of patients with advanced-stage, ipilimumab-refractory melanoma, 26% of participants treated with pembrolizumab, an anti-PD-1 antibody, demonstrated either a complete or partial response (57).”
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- Interpretationnone given
The composition of immune cells within tumors and in the periphery before and after therapy is among the most prominent predictive markers of ICI efficacy.
“Perhaps the most prominent predictive markers of effective ICI therapy are the compositions of immune cells within tumors and in the periphery in patients prior to and after therapy.”
Quote in the paperNot a substantial claim - Premisecitation
Atezolizumab was initially approved for localized and metastatic urothelial carcinoma based on a phase II trial showing 10% overall response rate in patients progressing after platinum-based chemotherapy.
“Atezolizumab was initially approved by the FDA for the treatment of localized and metastatic urothelial carcinoma on the basis of results of a phase II clinical trial that showed overall response rates of 10% in patients whose disease had progressed after platinumbased chemotherapy treatment (65).”
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- Interpretationreasoning
Peripheral immune responses are critical for favorable clinical outcomes after ICI therapy.
“In fact, peripheral immune responses are critical in achieving favorable clinical outcomes.”
Quote in the paperNot a substantial claim - Premisenone given
ICIs activate not only T cells but also other innate and adaptive immune cells that cooperate against tumors.
“ICIs work not only by invigorating T cells but also by activating other cells of the innate and adaptive arms, all of which function in concert to orchestrate an effective response against tumors.”
Quote in the paperNot a substantial claim
- Premisecitation
Most patients and cancers do not respond to ICIs.
“Despite the fact that many patients experience dramatic tumor regression in response to ICIs, most patients and cancers do not respond to these therapies.”
- Also stated in: § RESISTANCE TO IMMUNE CHECKPOINT INHIBITORS · plain
“only a minority of patients treated with ICIs achieve a durable response.”
Quote in the paperSubstantial claim0 of 2 sources checked - Also stated in: § RESISTANCE TO IMMUNE CHECKPOINT INHIBITORS · plain
- Premisecitation
Resistance to ICIs limits the number of patients who achieve durable responses.
“However, despite the success of ICIs, resistance to these agents restricts the number of patients able to achieve durable responses”
- Also stated in: § RESISTANCE TO IMMUNE CHECKPOINT INHIBITORS · plain
“only a minority of patients treated with ICIs achieve a durable response.”
Quote in the paperSubstantial claim0 of 2 sources checked - Also stated in: § RESISTANCE TO IMMUNE CHECKPOINT INHIBITORS · plain
- Premisecitation
Engagement of PD-1 with PD-L1 or PD-L2 suppresses T cell immune responses.
“Similar to CTLA-4, engagement of PD-1 with its ligands, PD-L1 and PD-L2, leads to suppression of T cell immune responses (36,37).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisenone given
ICI-driven immune changes occur both inside tumors and in peripheral organs such as draining lymph nodes and blood.
“ICI-driven changes in the immune response are observed both within tumors and in peripheral organs, such as the draining lymph nodes and peripheral blood.”
Quote in the paperNot a substantial claim - Premisecitation
Anti-PD-1 therapy received first-in-class FDA approval as a tissue-agnostic therapy for unresectable or metastatic tumors with microsatellite instability or deficient mismatch repair.
“The potency of anti-PD-1 in the clinic was further proved by its recent, first-in-class FDA approval as a tissueagnostic therapy for any unresectable or metastatic tumors exhibiting microsatellite instability or deficient mismatch repair (62).”
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- Premisecitation
Atezolizumab combined with chemotherapy is FDA-approved for squamous and nonsquamous NSCLC, small cell lung cancer, and PD-L1-positive triple-negative breast cancer.
“to date, atezolizumab, in combination with chemotherapy, has been approved by the FDA for the treatment of squamous and nonsquamous NSCLC, small cell lung cancer, and PD-L1-positive triple-negative breast cancer (66)(67)(68)(69).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation
PD-L1 and PD-L2 are expressed on hematopoietic and nonhematopoietic cells, including APCs and cancer cells.
“Both PD-L1 and PD-L2 are expressed on hematopoietic and nonhematopoietic cells, including APCs and cancer cells (36,37).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationnone given
The mechanisms of primary and acquired resistance to ICIs are not fully understood.
“Although we do not yet fully understand the mechanisms responsible for either form of resistance”
- Also stated in: § Acquired Resistance · plain
“Unlike primary resistance to ICIs, acquired resistance, also known as secondary resistance, is not as well understood.”
Quote in the paperSubstantial claim - Also stated in: § Acquired Resistance · plain
- Premisecitation
CTLA-4 suppresses T cell activity through both T cell-intrinsic and T cell-extrinsic mechanisms.
“CTLA-4 inhibits T cell activity through both T cell-intrinsic and T cell-extrinsic mechanisms.”
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- cites [10] Chuang E, 1999, J. Immunol. source
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- Interpretationreasoning
PD-1 and CTLA-4 have biologically nonredundant roles in suppressing immune responses.
“The exact reason for this difference is not fully understood, but it is clear that PD-1 and CTLA-4 play biologically nonredundant roles in suppressing developing immune responses.”
Quote in the paperSubstantial claim - Premisenone given
Among initial ICI responders, some later develop acquired resistance and relapse.
“Of the patients who initially respond, some develop resistance at a later time and experience tumor relapse; such patients are described as having acquired resistance.”
- Also stated in: § RESISTANCE TO IMMUNE CHECKPOINT INHIBITORS · plain
“acquired resistance encompasses those cases in which patients initially responded to an ICI but later became refractory.”
Quote in the paperSubstantial claim - Also stated in: § RESISTANCE TO IMMUNE CHECKPOINT INHIBITORS · plain
- Premisecitation
In a phase III trial, more than 30% of advanced melanoma patients achieved objective response with pembrolizumab monotherapy versus 12% with ipilimumab alone.
“In the subsequent phase III clinical trial, more than 30% of patients with advanced melanoma achieved an objective response following pembrolizumab monotherapy compared with 12% of patients treated with ipilimumab alone (58).”
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- Premisecitation
PD-L1 blockade inhibits both PD-1/PD-L1 and PD-L1/CD80 cis interactions on dendritic cells, freeing CD80 to enhance T cell priming.
“This is not surprising given that PD-L1 blockade inhibits not only the PD-1/PD-L1 axis but also PD-L1/CD80 cis interactions on DCs, freeing more CD80 molecules to enhance T cell priming (63).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [63] source
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- Premisenone given
The anti-CTLA-4 antibody ipilimumab was the first immune checkpoint inhibitor approved by the FDA, for metastatic melanoma, in 2011.
“Starting with the approval of anticytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) for advancedstage melanoma in 2011”
- Also stated in: § INTRODUCTION · plain
“An antibody against cytotoxic T lymphocyte-associated protein 4 (CTLA-4) called ipilimumab was the first to receive approval for the treatment of metastatic melanoma.”
Quote in the paperNot a substantial claim - Also stated in: § INTRODUCTION · plain
- Interpretationreasoning
Primary resistance to ICIs can occur when critical signaling pathways are disrupted in the tumor.
“Beyond low mutational burden, primary resistance to checkpoint therapies can also occur if critical signaling pathways are disrupted in the tumor.”
Quote in the paperSubstantial claim - Interpretationreasoning
Mutations in critical antitumor pathways such as IFN-γ and antigen presentation can cause primary resistance to ICIs.
“Thus, mutations in critical antitumor pathways, such as in IFN-γ and antigen presentation, can be a source of primary resistance to ICIs.”
Quote in the paperSubstantial claim - Interpretationnone given
The difference in understanding between primary and acquired resistance is considerable.
“Although other potential mechanisms of acquired resistance have been proposed and examined in preclinical studies, it is clear that the difference in our understanding of primary resistance and of acquired resistance is considerable.”
Quote in the paperSubstantial claim - Interpretationreasoning
Low tumor mutational burden is commonly associated with resistance or nonresponsiveness to ICIs.
“Thus, as a general observation, tumor types exhibiting low tumor mutational burdens are commonly associated with resistance or nonresponsiveness to ICIs.”
Quote in the paperSubstantial claim - Interpretationcitation
Whether the epigenetic landscape of tumor cells or T cell exhaustion contributes to ICI resistance is not well understood.
“However, whether the epigenetic landscape of the tumor cells or T cell exhaustion is contributing to resistance is not well understood, leaving much room for further understanding of how epigenetics can lead to nonresponse to ICIs (108, 109).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
PD-L1 expression intensity on tumor cells is a commonly used biomarker positively correlated with ICI response in several cancers.
“One of the most commonly used biomarkers for predicting response to ICIs is the intensity of PD-L1 expression on tumor cells, which is positively correlated with response to ICIs in several cancer settings (74,75,80).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
MEX3B, which downregulates MHC I, is expressed at higher levels in nonresponders to anti-PD-1 than in responders.
“For example, MEX3B, a gene responsible for downregulating MHC I expression in tumors, was expressed at higher levels in nonresponders to anti-PD-1 than in responders (96).”
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- Interpretationreasoning
Low mutational load, and therefore low neoantigen availability, is a major contributor to primary resistance to ICIs.
“Notwithstanding these exceptions, low mutational load, and therefore low availability of neoantigens, is a major contributor to primary resistance to ICIs.”
Quote in the paperSubstantial claim - Premisecitation
Similar MHC I presentation disruptions in lung cancer implicate dysregulated antigen presentation as a potent mediator of acquired resistance.
“Similar disruptions in MHC I presentation in patients with lung cancer were also reported, implicating dysregulated antigen presentation as a potent mediator of acquired resistance (111).”
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- Premisecitation
In the same study, another relapsed patient had a frameshift deletion of B2M, disrupting MHC I trafficking and rendering tumor cells invisible to cytotoxic CD8+ T cells.
“In the same study, tumor cells in another patient demonstrating relapse contained a frameshift deletion of β 2 -microglobulin (B2M), disrupting MHC I trafficking to the cell surface and thereby rendering the tumor cells invisible to cytotoxic CD8 + T cells (110).”
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- Interpretationreasoning
A patient's overall microflora makeup may contribute to primary resistance and response to ICIs.
“Thus, a patient's overall microflora makeup may contribute to primary resistance, as well as response, to ICIs.”
Quote in the paperSubstantial claim - Premisecitation
Fecal transplants from patients who benefited from anti-CTLA-4 favored growth of B. fragilis, linking this species with improved response.
“In addition, fecal transplants from patients who benefitted clinically from anti-CTLA-4 therapy favored the growth of B. fragilis, linking this species with improved response.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [99] source
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- Premisecitation
Similar microbiome findings for anti-PD-1 therapy have been reported, though different microbes are implicated.
“Similar findings for anti-PD-1 therapy have been reported, although different microbes have been implicated (100, 101).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premiseown data
Anti-PD-1 antibodies have received the greatest number of FDA approvals among ICIs.
“As shown in Table 1, ICIs are approved for various cancer types, with anti-PD-1 antibodies having received the greatest number of approvals.”
Quote in the paperNot a substantial claim - Premisecitation
In 2018, only an estimated 12.5% of patients eligible for ICI therapy would have benefited.
“Of all the patients who met the eligibility criteria for ICI therapy in 2018, only an estimated 12.5% would have benefitted (79).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [79] source
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- Interpretationnone given
Our understanding of acquired resistance is too undeveloped to determine whether initial responders use different evasion strategies.
“Although our understanding of acquired resistance is far too undeveloped to determine whether this is the case”
Quote in the paperSubstantial claim - Interpretationcitation
One proposed mechanism of acquired resistance is evolution or selection of tumors with mutations in critical checkpoint response pathways.
“One mechanism purporting to contribute to the development of acquired resistance is evolution or selection of tumors that acquire mutations in critical pathways involved in the checkpoint blockade response.”
Quote in the paperSubstantial claim - Premisecitation
A strong IFN-γ signature predicts and indicates response in anti-PD-1-treated patients across various cancers.
“In the clinic, a strong IFN-γ signature has been identified as a useful predictor and indicator of response in anti-PD-1-treated patients across various cancer indications (75,92,93).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationnone given
Acquired resistance to ICIs is less well understood than primary resistance.
“Unlike primary resistance to ICIs, acquired resistance, also known as secondary resistance, is not as well understood.”
Quote in the paperNot a substantial claim - Interpretationreasoning
High neoantigen load is the common feature that potentiates ICI response in tumors with high mutational burden, increasing tumor visibility and antitumor T cell response.
“The common thread that unites these types of tumors and that potentiates their response to ICIs is their high neoantigen load, which leads to increased visibility of the tumor to the immune system and the development of a more potent antitumor T cell response following ICI treatment.”
Quote in the paperSubstantial claim - Premisecitation
Tumors with low mutational burdens, such as prostate and pancreatic cancers, respond poorly to ICIs.
“Given this contribution of mutational burden to ICI efficacy, tumors with low mutational burdens, such as prostate and pancreatic cancers, might be expected to respond poorly to ICIs, and this is indeed the case (88).”
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- Premisecitation
Higher tumor mutational loads are strongly associated with response to anti-CTLA-4 and anti-PD-1 across multiple cancer indications.
“Another well-recognized biomarker that predicts response or nonresponse to ICIs is the mutational burden of the tumor, with higher tumor mutational loads strongly associated with response to both anti-CTLA-4 and anti-PD-1 across multiple cancer indications (83)(84)(85)(86).”
Quote in the paperSubstantial claim0 of 4 sources checked - Premisecitation
Checkpoint therapy has been reported to cause new autoimmune diseases, such as type I diabetes, in patients without prior history of the disease.
“Newly developed autoimmune disease, such as type I diabetes in patients with no prior history of the disease, following checkpoint therapy has also been reported to occur”
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Development of vitiligo is associated with improved objective response rates and overall survival in melanoma patients treated with immune checkpoint inhibitors.
“Several studies have shown an association between development of vitiligo and improved objective response rates and overall survival in patients with melanoma (124-126).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Nonresponders to PD-1 treatment exhibited lower levels of CD69 and lower production of MIP-1β by NK cells.
“nonresponders to PD-1 treatment exhibited lower levels of CD69 and lower production of MIP-1β by NK cells (137).”
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- Interpretationcitation
The frequency and severity of immune-related adverse events differ between immune checkpoint modalities, with anti-PD-1 typically having a more favorable safety profile than anti-CTLA-4.
“The frequency and severity of irAEs differ between different immune checkpoint modalities, with anti-PD-1 typically exhibiting a more favorable safety profile compared with anti-CTLA-4.”
Quote in the paperNot a substantial claim - Premisecitation
Anti-CTLA-4 and anti-PD-1 treatments are associated with distinct predictive biomarkers in peripheral blood of melanoma patients.
“anti-CTLA-4 and anti-PD-1 treatments are associated with distinct predictive biomarkers.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [137] source
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- Premisecitation
In NSCLC, the favorable correlation between CD8+PD-1hi T cells and response was attributed to tumor reactivity and secretion of CXCL13, which recruited B cells and T follicular helper cells that may participate in antitumor responses.
“the favorable correlation between CD8 + PD-1 hi T cells and response to treatment was attributed not only to their tumor reactivity but also to their secretion of the chemokine CXCL13, which contributed to the recruitment of other immune cells, such as B cells and T follicular helper cells, that may participate in antitumor responses (147).”
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- Premisecitation
Numerous studies of immune checkpoint inhibitor-treated patients have highlighted the importance of immune cells both at the tumor site and in the periphery.
“numerous studies of ICI-treated patients have highlighted the importance of immune cells both at the tumor site and in the periphery.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [131] source
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- Premisecitation
Studies claiming improved outcomes associated with immune-related adverse events exist alongside studies reporting no apparent correlation, regardless of immune checkpoint inhibitor type.
“Studies claiming improved outcomes associated with irAEs can be found alongside studies reporting no apparent correlation, regardless of the type of ICI used (120, 127-130).”
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Immune checkpoint inhibitors can cause immune-related adverse events that range from mild rash to severe colitis to life-threatening myocarditis.
“overactivation of the immune system to boost antitumor immunity can act as a double-edged sword, leading to the development of irAEs that can range from mild rash to severe colitis to life-threatening myocarditis (114, 115).”
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In that mouse model, these systemic changes were critical to the antitumor response, as fingolimod abrogated the effect of immunotherapy.
“These changes throughout the host were critical to the antitumor response, as administration of fingolimod, a small molecule that inhibits egress of lymphocytes from the lymph nodes, abrogated the effect of the immunotherapy.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [131] source
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- Premisecitation
Effector and memory CD8+ T cell and NK cell populations are implicated in beneficial outcomes.
“Examination of the lymphocytes that correlated with such beneficial outcomes has repeatedly implicated effector and memory CD8 + T cell and NK cell populations (136-141).”
Quote in the paperSubstantial claim0 of 6 sources checked - Premisecitation
Combination treatment of advanced melanoma with anti-CTLA-4 and anti-PD-1 markedly increased the incidence and severity of immune-related adverse events, with 55% of patients exhibiting high-grade events.
“Combination treatment of advanced melanoma with both anti-CTLA-4 and anti-PD-1 led to a marked increase in both the incidence and the severity of irAEs, with 55% of those patients exhibiting high-grade irAEs (59).”
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- Premisecitation
Approximately 10-20% of patients receiving immune checkpoint inhibitors experience grade 3 or 4 immune-related adverse events.
“approximately 10-20% experience more severe grade 3 or 4 irAEs”
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In general, discontinuation of immune checkpoint inhibitor therapy and subsequent treatment with immunosuppressive agents do not appear to negatively impact patient outcomes.
“In general, discontinuation of ICI therapy and subsequent treatment with immunosuppressive agents do not appear to negatively impact patient outcomes (120, 121).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Intratumoral memory-like CD8+ T cells are more strongly associated with response to immune checkpoint inhibitor therapy.
“intratumoral memory-like CD8 + T cells were also more strongly associated with response to ICI therapy.”
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- Premisecitation
Decreased expression of PD-1 on these CD8+ T cells during therapy was a hallmark of better treatment outcome.
“decreased expression of PD-1 on these CD8 + T cells during therapy was a hallmark of better treatment outcome (143).”
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- Premisereasoning
Examination of blood and tumors from patients has revealed several biomarkers that correlate with clinical outcome.
“examination of blood and tumors from patients has revealed several biomarkers that correlate with clinical outcome.”
Quote in the paperSubstantial claim - Premisecitation
Proliferation of circulating CD8+PD-1hi CTLA-4+ T cells within 3-4 weeks of immune checkpoint inhibitor treatment was associated with responders in melanoma and NSCLC patients.
“proliferation of circulating CD8 + PD-1 hi CTLA-4 + T cells, within 3-4 weeks of ICI treatment, was also associated with responders in patients with melanoma and patients with NSCLC (148, 149).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
In mammary tumor-bearing mice, effective immunotherapy was characterized by marked changes in immune cells in the tumor and in peripheral organs such as draining lymph nodes, blood, and bone marrow.
“upon immunotherapy administration in mammary tumor-bearing mice, effective therapy was characterized by marked changes in immune cells not only in the tumor but also in peripheral organs such as the draining lymph nodes, blood, and bone marrow (131).”
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- Premisecitation
30-60% of patients receiving immune checkpoint inhibitors experience immune-related adverse events of any grade.
“30-60% of patients experience irAEs of any grade”
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Frequency of CD8+ effector memory cells in peripheral blood of advanced melanoma patients 9 weeks after anti-CTLA-4 treatment correlated with clinical benefit and overall survival.
“the frequency of CD8 + effector memory cells in the peripheral blood of patients with advanced melanoma 9 weeks after anti-CTLA-4 treatment correlated with clinical benefit and overall survival (142).”
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- Interpretationcitation
Systemic administration of immune checkpoint inhibitors affects not just T cells but also other immune cells throughout the body.
“Systemic administration of ICIs impacts not just T cells but also other immune cells throughout the body.”
Quote in the paperSubstantial claim - Premisenone given
Invasive studies of immune cell contributions cannot be carried out in patients, unlike preclinical models.
“these sorts of invasive studies cannot be carried out in patients.”
Quote in the paperNot a substantial claim - Premisecitation
Clinical studies of immune checkpoint inhibitor-treated patients highlight a potential role for CD4+ T cells in antitumor immunity.
“several clinical studies of patients treated with ICIs have highlighted a potential role for CD4 + T cells in antitumor immunity.”
Quote in the paperSubstantial claim - Premisecitation
Low absolute monocyte count in circulation is associated with better ipilimumab therapy outcome in melanoma patients.
“a low absolute monocyte count in circulation is associated with better ipilimumab therapy outcome in patients with melanoma.”
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- Interpretationcitation
Many new posttreatment clonotypes infiltrating the tumor could be identified in the blood, implicating the importance of peripheral T cell activation in the developing antitumor response.
“many of the new posttreatment clonotypes infiltrating the tumor could be identified in the blood, implicating the importance of T cell activation in the periphery in the developing antitumor response.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [164] source
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- Premisecitation
In melanoma patients, higher frequency of Tregs in lymph node metastases was associated with better response to ipilimumab compared with patients with fewer Tregs.
“Balatoni et al. (153) demonstrated that patients with melanoma who exhibited a higher frequency of Tregs in lymph node metastases responded better to ipilimumab compared with patients who had fewer Tregs (133).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationcitation
Immune checkpoint inhibitor treatment of patients induces significant immune changes both in the periphery and in the tumor site.
“ICI treatment of patients induces significant immune changes both in the periphery and in the tumor site.”
Quote in the paperSubstantial claim - Interpretationreasoning
Generating T cell responses to various tumor epitopes may help minimize tumor selection and eventual tumor escape.
“generating T cell responses to various tumor epitopes may help minimize tumor selection and eventual tumor escape.”
Quote in the paperSubstantial claim - Premisecitation
In preclinical models, macrophages and MDSCs aid tumor growth and metastasis by secreting factors that suppress antitumor immune responses, especially those of CD8+ T cells and NK cells.
“In preclinical models, both of these innate immune cell types aid tumor growth and metastasis through their secretion of factors that suppress antitumor immune responses, especially those of CD8 + T cells and NK cells (166, 167).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationcitation
Effective immune checkpoint inhibitor response may depend on an influx of novel, less exhausted T cells into the tumor site, contrary to the concept of in situ reinvigoration of exhausted CD8+ T cells.
“This finding suggests that, contrary to the concept of in situ reinvigoration of exhausted CD8 + T cells that was widely considered to be the mechanism of ICI therapy, an effective ICI response may actually depend on an influx of novel, less exhausted T cells into the tumor site.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [164] source
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- Premisecitation
In castration-resistant prostate cancer or advanced melanoma, patients who maintained oligoclonal circulating baseline TCRs after anti-CTLA-4 responded better than those who lost more clonotypes.
“patients with castration-resistant prostate cancer or advanced melanoma who maintained their oligoclonal circulating baseline TCRs after receiving anti-CTLA-4 responded better to therapy than those in which more of those clonotypes were lost (163).”
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- Interpretationcitation
Assessing T cell diversity or clonality in the blood may be useful for understanding the T cell profile in the tumor, as the periphery is implicated as the source of newly infiltrated T cells in the tumor.
“These studies also put forth the idea that assessing T cell diversity or clonality in the blood may be useful for understanding the T cell profile in the tumor, as Yost et al. and Wu et al. implicate the periphery as the source of newly infiltrated T cells in the tumor.”
Quote in the paperSubstantial claim - Interpretationcitation
Increased abundance of CD8+ T cells and memory-like CD8+ T cells in peripheral and tumor tissues before or after therapy is correlated with favorable response to immune checkpoint inhibitors.
“Overall, these studies support the concept that increased abundance of CD8 + T cells and CD8 + T cells with memory-like phenotypes in peripheral and tumor tissues prior to or after initiation of therapy is correlated with a favorable response to ICIs.”
Quote in the paperSubstantial claim - Premisecitation
In advanced melanoma, patients who responded to anti-PD-1 demonstrated lower tumoral macrophage infiltration.
“patients who responded to anti-PD-1 demonstrated lower tumoral macrophage infiltration (161).”
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- Interpretationreasoning
Frequency of CD4+ T cell populations prior to therapy and dynamic changes during therapy can serve as predictive biomarkers distinguishing immune checkpoint inhibitor responders from nonresponders.
“it is clear that the frequency of CD4 + T cell populations prior to therapy and the dynamic changes they undergo during therapy can serve as important predictive biomarkers distinguishing ICI responders from nonresponders.”
Quote in the paperSubstantial claim - Premisecitation
CD14+CD16-HLA-DRhi monocytes in peripheral blood at baseline were a strong predictor of progression-free and overall survival after anti-PD-1 antibody treatment in advanced melanoma.
“CD14 + CD16 -HLA-DR hi monocytes were a strong predictor of progression-free and overall survival after treatment with anti-PD-1 antibody.”
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- Premisecitation
In metastatic pancreatic cancer, longer survival is associated with lower baseline circulating clonality and a high number of expanded clones following anti-CTLA-4 treatment but not anti-PD-1 treatment.
“in patients with metastatic pancreatic cancer, longer survival has been associated with lower baseline circulating clonality and a high number of expanded clones following anti-CTLA-4 treatment but not anti-PD-1 treatment (162).”
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- Premisecitation
Higher ratio of effector CD8+ T cells to Tregs in tumors of previously vaccinated melanoma patients correlated favorably with tumor necrosis.
“a higher ratio of effector CD8 + T cells to Tregs in the tumors of previously vaccinated patients with melanoma correlated favorably with tumor necrosis (155).”
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- Premisecitation
In basal cell carcinoma and squamous cell carcinoma treated with anti-PD-1, posttreatment tumor TCR clones included many not present prior to therapy.
“In patients with basal cell carcinoma and patients with squamous cell carcinoma treated with anti-PD-1, TCR clones present in the tumor posttreatment consisted of a significant number of clones that were not present in the tumors prior to ICI therapy (164).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [164] source
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- Premisecitation
In cancer patients, myeloid cell subsets (macrophages, MDSCs) in tumor or peripheral tissues are negatively correlated with effective immune checkpoint inhibitor therapy.
“numerous studies of patients with cancer have indeed found that these myeloid cell subsets, whether in the tumor or in peripheral tissues, were negatively correlated with effective ICI therapy (134, 161, 168-171).”
Quote in the paperSubstantial claim0 of 6 sources checked - Premisecitation
Abundance of Tregs in blood of melanoma patients at baseline correlated with favorable outcome following ipilimumab treatment.
“an abundance of Tregs in the blood of patients with melanoma at baseline correlated with a favorable outcome following ipilimumab treatment (135).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [135] source
Not checked in the free run.
- Premisecitation
Location and functional status of intratumoral CD8+ T cells correlate with immune checkpoint inhibitor therapy outcome.
“The location and functional status of CD8 + T cells within tumors have also been correlated with ICI therapy outcome.”
Quote in the paperSubstantial claim - Premisecitation
In melanoma tumor biopsies, responders had higher frequency of memory CD4+ T cells (CCR7, CD28, CD62L) at baseline.
“responders had a higher frequency of memory CD4 + T cells, as defined by expression of CCR7, CD28, and CD62L (144).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [144] source
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- Premisecitation
In melanoma patients treated with ipilimumab, heightened frequency of CD4+ T cells in blood 8-14 weeks after first dose correlated with increased overall survival.
“An early study of patients with melanoma treated with ipilimumab showed that 8-14 weeks after the first dose, a heightened frequency of CD4 + T cells in blood correlated with increased overall survival (135).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [135] source
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- Premisecitation
In bladder cancer, CTLA-4 blockade led to increased ICOS expression on IFN-γ producing CD4+ T cells.
“in patients with bladder cancer, CTLA-4 blockade led to increased inducible T cell costimulator (ICOS) expression on IFN-γ producing CD4 + T cells.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [156] source
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- Premisecitation
Low baseline frequency of MDSCs and low frequency of MDSCs in blood of melanoma patients following ipilimumab treatment were associated with favorable therapy outcome.
“both a low baseline frequency of MDSCs and a low frequency of MDSCs in the blood of patients with melanoma following ipilimumab treatment were associated with favorable therapy outcome (134, 169-171).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation
Decreases in Tregs in peripheral blood and tumors of metastatic melanoma patients treated with immune checkpoint inhibitors are associated with ICI response and increased patient survival.
“decreases in Tregs in the peripheral blood and tumors of patients with metastatic melanoma treated with ICIs have been associated with ICI response and increased patient survival”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Increased proportion of circulating Tregs in melanoma patients after anti-PD-1 therapy correlated with favorable response.
“an increased proportion of circulating Tregs in patients with melanoma after treatment with anti-PD-1 therapy correlated with a favorable response.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [154] source
Not checked in the free run.
- Premisecitation
Lack of PD-1 downregulation on CD4+PD-1hi T cells after anti-PD-1 treatment resulted in higher risk of death in advanced melanoma patients.
“lack of PD-1 downregulation on CD4 + PD-1 hi T cells following treatment with anti-PD-1 resulted in a higher risk of death in patients with advanced melanoma (152).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [152] source
Not checked in the free run.
- Premisecitation
Decrease in abundance of tumor-infiltrating macrophages in melanoma patients treated with anti-CTLA-4 and anti-PD-1 antibodies distinguished responders from nonresponders.
“a decrease in the abundance of tumor-infiltrating macrophages in patients with melanoma treated with anti-CTLA-4 and anti-PD-1 antibodies distinguished responders from nonresponders (172).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [172] source
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- Premisecitation
A study suggested a peripheral origin for intratumoral CD8+ clonotypes based on expanded clones infiltrating the tumor, normal adjacent tissue, and blood.
“a study performed by Wu et al. (165) that similarly suggested a peripheral origin for intratumoral CD8 + clonotypes, on the basis of the presence of expanded clones infiltrating the tumor as well as normal adjacent tissue and blood.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [165] source
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- Premisecitation
Increased abundance of ICOS+ CD4+ T cells resulted in an increased ratio of these cells to Tregs in tumor and peripheral blood.
“The increased abundance of ICOS + CD4 + T cells resulted in an increased ratio of these cells to Tregs (156) both in the tumor and in peripheral blood.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [156] source
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- Premisecitation
In that study, no TCR parameters were associated with clinical outcomes in patients treated with anti-PD-1.
“no TCR parameters were found to be associated with clinical outcomes in patients treated with anti-PD-1.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [162] source
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- Premisecitation
Increased frequencies of CD62L low CD4+ T cells in circulation of NSCLC patients before anti-PD-1 treatment were predictive of greater progression-free survival.
“increased frequencies of CD62L low CD4 + T cells in the circulation of patients with NSCLC before treatment with anti-PD-1 were predictive of greater progression-free survival following ICI treatment.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [151] source
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- Premisecitation
Immune checkpoint inhibitors are not the only FDA-approved immunotherapies.
“although ICIs are the most widely used, they are not the only FDA-approved immunotherapies.”
Quote in the paperNot a substantial claim0 of 2 sources checked
- May combine two claims. 40
- Classified as probably not a substantial claim. 5
May combine two claims.
PremisecitationIn a phase III trial of previously untreated unresectable stage III/IV melanoma, progression-free survival was highest with nivolumab plus ipilimumab, intermediate with nivolumab alone, and lowest with ipilimumab alone.
“At the end of the trial, progression-free survival was highest in patients who received the combination therapy, followed by patients treated with nivolumab alone, and was lowest in patients treated with ipilimumab alone (59).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [59] source
Not checked in the free run.
May combine two claims.
Premisenone givenImmune-related adverse events complicate ICI treatment and can be life-threatening.
“immune-related adverse events complicate treatment.”
- Also stated in: § PD-1 and PD-L1 · plain
“a large proportion of ICI-treated patients develop immune-related adverse events (irAEs), some of which can be life-threatening.”
Quote in the paperSubstantial claim- Also stated in: § PD-1 and PD-L1 · plain
May combine two claims.
PremisecitationAfter TCR signaling, CTLA-4 moves to the cell surface and competes with CD28 for the same ligands with higher affinity, reducing costimulation.
“Once TCR signaling is induced, intracellularly stored CTLA-4 molecules traffic to the cell surface, where they can bind and compete for the same ligands as CD28, but with greater affinity, thereby dampening costimulation (7,8).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationPD-1 is expressed on most activated immune cells and is most highly upregulated on exhausted T cells.
“Although PD-1 is expressed on the surface of most activated immune cells, such as macrophages, dendritic cells (DCs), Langerhans cells, B cells, and T cells, its expression is most highly upregulated on exhausted T cells (34,35).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Premisenone givenICIs targeting PD-1 and PD-L1 have received FDA approval for many cancer types and extend patient survival.
“ICIs-which now also include antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1)-quickly gained US Food and Drug Administration approval for the treatment of a wide array of cancer types, demonstrating unprecedented extension of patient survival.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationCTLA-4 is an inhibitory receptor expressed primarily by T cells that dampens T cell activity and is upregulated upon T cell activation.
“CTLA-4, an inhibitory receptor expressed primarily by T cells, functions to dampen T cell activity and is upregulated upon T cell activation (1)(2)(3).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisenone givenICIs release inhibitory brakes on T cells, causing robust immune activation and antitumor responses.
“ICIs work by releasing the inhibitory brakes of T cells, resulting in robust activation of the immune system and productive antitumor immune responses.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationPD-L1 and PD-L2 expression increases in cancerous tissues and is linked to poor prognosis in many cancer types.
“Subsequent human studies have consistently shown that PD-L1 and PD-L2 expression not only increases in cancerous tissues but is also linked to poor disease prognosis in many cancer types (50)(51)(52)(53)(54)(55)(56).”
Quote in the paperNot a substantial claim0 of 7 sources checked- cites [50] source
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- cites [51] source
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- cites [52] source
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- cites [53] source
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- cites [54] source
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- cites [55] source
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- cites [56] source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenPatients who never respond to ICIs have primary resistance.
“Patients who never experience a therapeutic response are described as having primary resistance.”
- Also stated in: § RESISTANCE TO IMMUNE CHECKPOINT INHIBITORS · plain
“Primary resistance refers to those cases in which no initial response to checkpoint therapy was observed”
Quote in the paperNot a substantial claim- Also stated in: § RESISTANCE TO IMMUNE CHECKPOINT INHIBITORS · plain
Classified as probably not a substantial claim.
InterpretationcitationCombining ICIs may achieve maximum antitumor efficacy.
“This stratification in progression-free survival hinted at the possibility of combining ICIs to achieve maximum antitumor efficacy.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn that trial, 20% of patients whose tumors were completely cleared maintained response for the study duration, with median follow-up about 30 months.
“Critically, analogous to what was observed in preclinical studies, the 20% of patients whose tumors were completely cleared maintained their response for the duration of the study, with a median follow-up time of approximately 30 months.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] source
Not checked in the free run.
May combine two claims.
PremisecitationAmong melanoma patients, 60-70% do not have an objective response to anti-PD-1 therapy; of responders, 20-30% eventually relapse.
“Even among patients with melanoma, which has one of the highest rates of response to ICI, 60-70% of patients do not experience an objective response to anti-PD-1 therapy; of those that do, 20-30% demonstrate eventual tumor relapse and progression (74,75).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationIn preclinical models, anti-CTLA-4 response depends on Bacteroides species; germfree or antibiotic-treated mice do not respond, but response is rescued by B. fragilis gavage.
“For example, in preclinical models, the therapeutic response to anti-CTLA-4 therapy was found to be dependent on Bacteroides species, as germfree mice or antibiotic-treated mice did not respond to anti-CTLA-4, but response was rescued through gavage of Bacteroides fragilis (99).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [99] source
Not checked in the free run.
May combine two claims.
PremisecitationPD-L1-negative tumors can occasionally respond to anti-PD-1, and high PD-L1 expression is not sufficient for response.
“However, PD-L1-negative tumors can still occasionally respond to anti-PD-1 therapy, and high PD-L1 expression, although correlative, is by no means sufficient for generating a response following anti-PD-1 therapy, indicating that other factors are involved in determining response and nonresponse to ICIs (80)(81)(82).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationThe cause of high mutational burden does not determine ICI response; melanoma and NSCLC with UV/carcinogen mutations respond as well as tumors with genomic instability or deficient mismatch repair.
“The underlying cause of the high mutational burden is not important for determining whether a tumor will respond to ICIs, as melanoma and NSCLC, which acquire mutations through UV-and carcinogen-induced DNA damage, respectively, respond just as well to ICIs as do tumors that acquire mutations through genomic instability or deficient mismatch repair (74,80,87).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationMHC I downregulation via transcriptional repression is associated with primary resistance to anti-CTLA-4 but not anti-PD-1; anti-PD-1 response depends more on MHC II expression linked to an IFN-γ-regulated gene module.
“In another study, MHC I downregulation via transcriptional repression was associated with primary resistance to anti-CTLA-4 therapy but not to anti-PD-1 therapy, and the response to anti-PD-1 was more dependent on MHC II expression linked to an IFN-γ-regulated module of genes (97).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [97] source
Not checked in the free run.
May combine two claims.
Premisenone givenSome patients who receive ICIs do not respond (primary resistance), while others respond initially but eventually relapse (acquired resistance).
“Some patients who receive ICIs do not respond to treatment (primary resistance), while others respond to initial therapy but eventually relapse (acquired resistance).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMutations in SWI-SNF chromatin remodeling complex genes may sensitize human tumors to ICIs, and epigenetic modulators can potentiate ICI response by increasing chemokines that recruit CD8+ T cells.
“Several studies have demonstrated that mutations in genes involved in the SWI-SNF chromatin remodeling complex may sensitize human tumors to ICIs and that treatment with an epigenetic modulator can potentiate the ICI-mediated antitumor response through increased production of chemokines responsible for recruiting CD8 + T cells (104-107).”
Quote in the paperSubstantial claim0 of 4 sources checkedMay combine two claims.
PremisecitationResponse rates to ICIs vary widely across cancers, from >80% in refractory Hodgkin's lymphoma to little or no response in mismatch repair-proficient colorectal cancer, with many indications at 20-40%.
“Response rates to ICI treatment vary widely among different cancers, ranging from greater than 80% in patients with refractory Hodgkin's lymphoma to little or no response in patients with mismatch repair-proficient colorectal cancer (76, 77); many tumor indications fall within a response rate range of 20% to 40% (78).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationDurvalumab and avelumab are approved for urothelial carcinoma, and avelumab is approved for Merkel cell carcinoma.
“Apart from atezolizumab, durvalumab and avelumab are also approved for use in patients with urothelial carcinoma (70)(71)(72), and avelumab is approved for use in patients with Merkel cell carcinoma (73).”
Quote in the paperNot a substantial claim0 of 4 sources checkedMay combine two claims.
InterpretationcitationTumors with absent or low PD-L1 expression are more likely to be resistant to anti-PD-1/PD-L1, supported by response rates up to 10% in PD-L1-low melanoma and NSCLC versus 40-50% in high PD-L1.
“Thus, it stands to reason that tumors with absent or low expression of PD-L1 are more likely to exhibit resistance to anti-PD-1 and anti-PD-L1 therapies, and this assertion is supported by response rates of only up to 10% in patients with PD-L1-low melanoma and patients with NSCLC treated with anti-PD-1 compared with 40-50% in patients with high PD-L1 expression (74,80).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationICI-treated patients who received antibiotics have decreased overall survival and progression-free survival.
“This idea is further supported by reports of decreased overall survival and progression-free survival in ICI-treated patients who received antibiotics (101-103).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationIFN-γ is important for initiating and maintaining antitumor responses by promoting CD8+ cytotoxic T cell activity, Th1 skewing, antiproliferative/proapoptotic effects, and MHC I upregulation on tumor cells.
“Interferon-γ (IFN-γ) is an important cytokine for initiating and maintaining a potent antitumor response not only through promoting CD8 + cytotoxic T cell activity and skewing toward a Th1 response but also through exerting antiproliferative, proapoptotic effects and inducing major histocompatibility complex class I (MHC I) upregulation in tumor cells (90,91).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationPresence of CD8+PD-1hi T cells in tumors of melanoma and NSCLC patients prior to anti-PD-1 administration was predictive of treatment response and correlated with overall survival.
“the presence of CD8 + PD-1 hi T cells in the tumors of patients with melanoma and patients with NSCLC prior to anti-PD-1 administration was predictive of treatment response and correlated with overall survival (146, 147).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationIn untreated melanoma, anti-CTLA-4 caused grade 3 or 4 immune-related adverse events in 27.3% of patients, while anti-PD-1 caused such severe events in 16.3%.
“In patients with untreated melanoma, treatment with anti-CTLA-4 led to grade 3 or 4 irAEs in 27.3% of patients and treatment with anti-PD-1 led to such severe irAEs in only 16.3% of patients (59).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [59] source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe association between vitiligo and improved outcomes may be stronger than for other immune-related adverse events because the autoimmune reaction targets shared antigens between healthy melanocytes and melanoma cells, making vitiligo a surrogate for antitumor response.
“This association may be stronger than those with other irAE manifestations due to the autoimmune reaction targeting shared antigens between healthy melanocytes and the melanoma cells, allowing the occurrence of vitiligo to serve as a surrogate measure of the developing antitumor response.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Interpretationnone givenSignificant effort has been devoted to understanding primary resistance, whereas studies of acquired resistance have begun only recently.
“Although significant effort has been devoted to understanding the mechanisms of primary resistance, studies of acquired resistance have begun only recently.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIncreased lymphocyte counts in the blood are associated with favorable treatment outcome and increased overall survival in melanoma patients treated with immune checkpoint inhibitors.
“increased lymphocyte counts in the blood are associated not only with favorable treatment outcome but also with increased overall survival in patients with melanoma treated with ICIs (132-135).”
Quote in the paperSubstantial claim0 of 4 sources checkedMay combine two claims.
PremisecitationThere are exceptions where immunosuppression may negatively impact outcomes, indicating a need for better understanding of the interplay between antitumor response and immunosuppressive agents.
“However, there are exceptions, indicating that better understanding of the interplay between the developing antitumor response following ICI therapy and the use of immunosuppressive agents is needed (117, 122, 123).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationA subset of peripheral effector-memory-like CD4+ T cells was associated with effective immunotherapy and could initiate an antitumor response upon adoptive transfer to untreated tumor-bearing mice.
“a subset of peripheral effector-memorylike CD4 + T cells was associated with effective immunotherapy and could initiate an antitumor response upon adoptive transfer to untreated tumor-bearing mice (131).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [131] source
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PremisecitationIn melanoma patients, CD45RA+ naive CD8+ T cells negatively correlated with ipilimumab response, while CD45RA- CD8+ T cells and CD8+ effector memory cells were more abundant in responders.
“Whereas CD45RA + naive CD8 + T cells negatively correlated with response with ipilimumab treatment, CD45RA -CD8 + T cells and CD8 + T effector memory cells (CD45RA -CCR7 -) were more abundant in responsive patients (137).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [137] source
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PremisecitationAnti-CTLA-4 and anti-PD-1 therapies differ in immune-related adverse event organ presentation: anti-CTLA-4 causes more hypophysitis and severe colitis, while anti-PD-1 causes more pneumonitis, thyroiditis, and nephritis.
“anti-CTLA-4 resulting in more hypophysitis and more severe colitis cases and anti-PD-1 resulting in more pneumonitis, thyroiditis, and nephritis cases (114, 118).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
InterpretationcitationThe differences in immune-related adverse event organ presentation may result from different mechanisms of T cell inhibition: CTLA-4 functions more proximally to T cell activation, and PD-1 functions at later stages in the periphery.
“These differences may be the result of the different mechanisms of T cell inhibition by CTLA-4 and PD-1, as the former is understood to function more proximally to T cell activation and the latter is thought to function at later stages in the periphery (119).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [119] source
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InterpretationcitationDuring tumor rejection, proliferating immune cells were present in draining lymph nodes but not in the tumor, suggesting that peripheral immune response is important for maintaining and activating antitumor immune cells.
“The tumor rejection phase was characterized by proliferating immune cells in the draining lymph nodes but not in the tumor, suggesting that the immune response in the periphery is important for maintaining and activating immune cells participating in the antitumor response.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [131] source
Not checked in the free run.
May combine two claims.
PremisecitationIn melanoma, higher frequency of memory CD45RA- CD4+ T cells at baseline was associated with favorable response to ipilimumab, while increased naive CD45RA+ CD4+ T cells correlated with nonresponders.
“a higher frequency of memory CD45RA -CD4 + T cells in the blood of patients with melanoma at baseline was associated with a favorable response to ipilimumab, whereas an increased presence of naive CD45RA + CD4 + T cells correlated with nonresponders (137).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [137] source
Not checked in the free run.
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PremisecitationSome studies found that high TCR diversity in peripheral blood and tumors prior to immune checkpoint inhibitor therapy is predictive of effective treatment, while others found that increases in TCR clonality are a sign of effective therapy.
“some studies have found that high TCR diversity in peripheral blood and tumors prior to ICI therapy is predictive of effective treatment, others have pointed to ICI therapy-associated increases in TCR clonality, that is, enrichment of T cells with the same TCRs, as a sign of effective therapy (150, 157-161).”
Quote in the paperSubstantial claim0 of 6 sources checkedMay combine two claims.
InterpretationreasoningIt is unlikely that quantifying a single cell population or parameter will accurately predict response or nonresponse to immune checkpoint inhibitor treatment, and a more holistic approach encompassing multiple cell types is necessary.
“it is unlikely that quantifying a single cell population or parameter will accurately predict response or nonresponse to ICI treatment, and a more holistic approach encompassing multiple cell types will be necessary.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningImmune checkpoint inhibitor therapy may bring about similar tumoral and systemic changes in immune cells, suggesting that circulating immune cells may provide a window into changes in immune cells in the tumor.
“this study nonetheless points to the possibility that ICI therapy brings about similar tumoral and systemic changes in immune cells, suggesting that circulating immune cells may provide a window into changes in immune cells in the tumor.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOne study suggested that anti-CTLA-4 mainly induces proliferation of ICOS+ CD4+ effector T cells, while anti-PD-1 is primarily associated with reinvigoration of CD8+PD-1hi T cells.
“One study, for example, has suggested that anti-CTLA-4 induces mainly proliferation of ICOS + CD4 + effector T cells and that anti-PD-1 is associated primarily with reinvigoration CD8 + PD-1 hi T cells (175).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [175] source
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InterpretationreasoningThe negative role for tissue macrophages and MDSCs in immune checkpoint inhibitor treatment is well established, while understanding of the role of circulating monocytes remains blurred.
“whereas the negative role for tissue macrophages and MDSCs in ICI treatment is well established, our understanding of the role of circulating monocytes remains blurred.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIncreased frequency of circulating monocytes at baseline predicts superior immune checkpoint inhibitor responses, unlike macrophages and MDSCs in tumors and other tissues.
“an increased frequency of circulating monocytes at baseline, unlike macrophages and MDSCs in tumors and other tissues, predicts superior ICI responses (174).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [174] source
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PremisecitationA DC vaccine for advanced prostate cancer and chimeric antigen receptor T cells for several hematological malignancies have received FDA approval.
“A DC vaccine for the treatment of advanced prostate cancer and chimeric antigen receptor T cells for the treatment of several hematological malignancies are among other immunotherapies that have also received FDA approval (176, 177).”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
Premisenone givenThe role of systemic immunity is not well understood in these other immunotherapies.
“the role of systemic immunity is not well understood in these modalities.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Lymphocytes, especially CD8+ T cells and NK cells, are critical for antitumor immunity.
“A paradigm in the field of tumor immunology is that lymphocytes, especially CD8 + T cells and NK cells, are critical for antitumor immunity.”
The paper relies on this without support.
For any T cell to become activated and acquire effector functions, its TCR must recognize its cognate antigen presented on an MHC molecule.
“For any T cell to become activated and acquire effector functions, its TCR must recognize its cognate antigen presented on an MHC molecule.”
The paper relies on this without support.
The antigen specificity of a T cell is determined by its TCR, and each cell expresses multiple copies of only a single TCR, making T cells highly specific.
“The antigen specificity of a T cell is determined by its TCR, and because each cell expresses multiple copies of only a single TCR, T cells are highly specific in their response.”
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?
Preclinical studies emphasizing the pivotal role of the PD-1/PD-L1 axis in suppressing effector T cell function led to FDA approval of nivolumab and pembrolizumab, monoclonal antibodies to PD-1, for various solid immunologically 'hot' cancers like melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma.
“Preclinical studies emphasizing the pivotal role of the PD-1/PD-L1 axis in suppressing effector T cell function led to FDA approval of nivolumab and pembrolizumab, monoclonal antibodies to PD-1, for various solid immunologically ‘hot’ cancers like melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (Bagchi et al., 2021).”
From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Bagchi et al., 2021
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIpilimumab, the first FDA-approved monoclonal antibody targeting the negative immune checkpoint protein CTLA-4, enhances T cell activation and depletes Tregs in the tumor bed.
“Ipilimumab, the first FDA-approved monoclonal antibody targeting the negative immune checkpoint protein CTLA-4, enhances T cell activation and depletes Tregs in the tumor bed (Bagchi et al., 2021).”
From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Bagchi et al., 2021
The Introduction identifies ipilimumab as the first FDA-approved antibody against CTLA-4, and the CTLA-4 section describes blockade of this inhibitory receptor as a way to boost T-cell antitumor responses. The section on local and systemic immune responses reports that lower tumor Treg levels have been associated with responses to immune checkpoint inhibitors, but it does not establish that ipilimumab itself depletes Tregs in the tumor bed. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSome studies reported that there might be phosphotyrosine-independent cooperation among SHP2 and CTLA4 as alternated tyrosine CTLA4 could interact with SHP2 and inhibit TCRζ signaling pathways.
“Some studies reported that there might be phosphotyrosine‐independent cooperation among SHP2 and CTLA4 as alternated tyrosine CTLA4 could interact with SHP2 and inhibit TCRζ signaling pathways [299, 300].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [299]
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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
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Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
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Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
Rizvi, N. A., Hellmann, M. D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J. J., Lee, W., Yuan, J., Wong, P., Ho, T. S., et al. (2015) · Science · doi:10.1126/science.aaa1348 · Cited by 7,802 · see citing works
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- Authors
- Bagchi, S., Yuan, R., & Engleman, E. G.
- Affiliations
- Stanford Medicine (US)
- Venue
- Annual Review of Pathology: Mechanisms of Disease
- Publisher
- Annual Reviews
- Published
- 2021-01-24
- Volume
- 16
- Issue
- 1
- Pages
- 223-249
- ISSN
- 1553-4006 (ISSN-L)
- 1553-4014
- OpenAlex
- W3106005610
- Semantic Scholar
- 58a498a336df510986c6c2190384da22c7b34f10
- Cited by
- 2,189
- References
- 176
- Citations by year
- 2026: 259 · 2025: 425 · 2024: 548 · 2023: 514 · 2022: 377 · 2021: 64
- FWCI
- 25.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annual Review of Pathology Mechanisms of Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA233958, U54CA209971, R01CA222969)
- 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 › T-cell and B-cell Immunology
- Keywords
- immune checkpoint inhibitors, cancer immunotherapy, CTLA-4, PD-1, PD-L1, immune resistance mechanisms, immune-related adverse events, antitumor immunity, combination immunotherapy, melanoma
- MeSH terms
- Immune Checkpoint Inhibitors, Animals, Humans, Immunotherapy, Neoplasms, Drug Resistance, Neoplasm
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 ›
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