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Cited by 970Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12

Open access
Garris, Christopher S., Arlauckas, Sean P., Kohler, Rainer H., Trefny, Marcel P., Garren, Seth, Piot, Cécile, Engblom, Camilla, Pfirschke, Christina +15 more·2018·Immunity
DOI 10.1016/j.immuni.2018.09.024PMC PMC6301092
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Abstract

&NA; Anti‐PD‐1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real‐time imaging with single‐cell RNA sequencing analysis and mouse models to uncover anti‐PD‐1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor‐infiltrating dendritic cells (DCs), which produced interleukin 12 (IL‐12). These DCs did not bind anti‐PD‐1 but produced IL‐12 upon sensing interferon &ggr; (IFN‐&ggr;) that was released from neighboring T cells. In turn, DC‐derived IL‐12 stimulated antitumor T cell immunity. These findings suggest that full‐fledged activation of antitumor T cells by anti‐PD‐1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN‐&ggr; and IL‐12. Furthermore, we found that activating the non‐canonical NF‐&kgr;B transcription factor pathway amplified IL‐12‐producing DCs and sensitized tumors to anti‐PD‐1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade. Graphical Abstract Figure. No caption available. HighlightsEffective anti‐PD‐1 anti‐tumor responses require IL‐12‐producing dendritic cellsAnti‐PD‐1 indirectly activates IL‐12 through IFN‐&ggr; produced from CD8+ T cellsAgonizing the non‐canonical NF‐&kgr;B pathway enhances dendritic cell IL‐12 productionCombining aPD‐1 with non‐canonical NF‐&kgr;B agonism enhances checkpoint immunotherapy &NA; Anti‐PD‐1 mAbs can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Garris et al. show that effective anti‐PD‐1 immunotherapy requires intratumoral dendritic cells (DCs) producing IL‐12. Anti‐PD‐1 indirectly activates DCs through IFN‐&ggr; released from drug‐activated T cells. Furthermore, agonizing the non‐canonical NF‐&kgr;B pathway activates DCs and enhances aPD‐1 therapy in an IL‐12‐dependent manner.

Integrity signals

Registry

Crossref · 10.1016/j.immuni.2018.09.024

Cites

61 of 61 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 21 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Stimulated CD8+ T cells from MC38 tumors produced substantially more IFN-γ in the presence of IL-12.

    “Stimulated CD8+ T cells substantially increased IFN-γ production in the presence of IL-12 (Figure 4C)”
    Quote in the paperSubstantial claim
  • Findingown data

    Anti-PD-1 did not induce detectable IFN-γ or IL-12 in the local draining lymph node.

    “we did not find evidence of IFN-γ or IL-12 induction by aPD-1 in the local draining lymph node (Figure S4A and B)”
    Quote in the paperSubstantial claim
  • Findingown data

    Flow cytometry showed the IL-12+ DC-like cells were MHC class II+ and F4/80-.

    “Flow cytometry analysis confirmed these cells to be MHC class II+ F4/80– (Figure S1D)”
    Quote in the paperSubstantial claim
  • Findingown data

    IL-12p40-eYFP+ cells had a branched morphology with a mean circularity index of 0.54 ± 0.4.

    “IL-12p40-eYFP+ cells displayed a branched morphology (mean circularity index: 0.54 ± 0.4), suggesting they were DCs.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Parabiosis of tumor-bearing mice indicated that IL-12+ DC-like cells could arise from a blood-circulating precursor.

    “parabiosis of tumor-bearing mice indicated that these cells could derive from a blood circulating precursor (Figure S1E).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 21
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    In MC38 tumor-bearing mice, a single anti-PD-1 injection expanded tumor IFN-γ-eYFP+ cells about 6.0-fold one day later, and this increase lasted up to three days.

    “Intravital imaging of the tumor microenvironment revealed a 6.0 ± 1.1 (mean ± SEM) fold expansion of IFN-γ- eYFP+ cells one day after a single aPD-1 injection; this increase was sustained for up to 3 days post treatment (Figure 1B and S1A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL-12+ cells were motile one day after anti-PD-1 with a motility coefficient around 10 μm2/min, and were much less motile on day five (<1 μm2/min).

    “The ability for IL-12+ cells to accumulate within tumors was supported by the real-time imaging observation that these cells were motile one day after aPD-1 treatment (motility coefficient: ~10 µm2/min; Figure 1G-H and Supplemental Video 1) and much less so on day five (<1 µm2/min; Figure 1G-H and Supplemental Video 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Both DC subsets were largely negative for Csf1r, though some DC2s expressed it, similar to a previously reported intratumoral DC subset.

    “Both DC subsets were largely negative for the macrophage colony-stimulating factor receptor Csf1r (Figure 2C), although some DC2s expressed this receptor (Figure S2A), similarly to a subset of intratumoral DCs previously reported (Broz et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Broz et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Both DC1 and DC2 expressed Batf3, Flt3, H2-Dmb2, and Zbtb46; DC1 expressed Fscn1 and Ly75, while DC2 expressed CD209a, Mgl2, and Cd24a.

    “Both DC1s and DC2s expressed the DC markers Batf3, Flt3, H2-Dmb2 and Zbtb46 (Meredith et al., 2012; Hildner et al., 2008;); DC1 expressed Fscn1 and Ly 75 (DEC-205) whereas DC2s expressed CD209a (DC- SIGN), Mgl2 (CD301b) and Cd24a (Figure 2B and Figure S2B).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Meredith et al., 2012 source

      Not checked in the free run.

    • cites Hildner et al., 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    DC1s and DC2s expressed distinct chemokines and chemokine receptors.

    “and DC1s and DC2s expressed distinct chemokines and chemokine receptors (Figure 2E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The reduction in IL-12 after IFN-γ blockade involved both decreased IL-12 production per DC and decreased numbers of IL-12+ DCs.

    “Decreased IL-12 production by DCs (Figure S3D) and decreased numbers of IL-12+ DCs (Figure S3E, F) both contributed to this reduction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Anti-PD-1 treatment increased IL-12p40-eYFP+ cells in MC38 tumors about 12.1-fold at day one, and the increase persisted for at least five days.

    “Intravital imaging further revealed a 12.1 ± 3.7 fold increase of IL-12p40-eYFP+ cells on day one post treatment, which persisted for at least five days (Figure 1C and S1C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    DC1s had higher Csf2rb expression than DC2s, and neither DC1s nor DC2s expressed Csf3r.

    “DC1s had higher expression of the granulocyte/macrophage colony-stimulating factor receptor Csf2rb compared to DC2s, and neither DC1s nor DC2s expressed the granulocyte colony-stimulating factor receptor Csf3r (Figure 2C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In this study's experimental setups, CD8+ T cells and DCs were the primary producers of IFN-γ and IL-12, respectively.

    “in the experimental setups used in this study we found that CD8+ T cells and DCs are the primary producers of IFN-γ and IL-12, respectively”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL-12+ cells had more surface CD40 than IL-12- counterparts, and IL-12+ DCs had more CD40 than TAMs.

    “We confirmed that IL-12+ cells had more cell surface CD40 than their IL-12– counterparts (Figure S6A) and that IL-12+ DCs expressed more CD40 than tumor-associated macrophages (Figure S6B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Treatment with agonistic anti-CD40 mAbs or AZD5582 provided antitumor effects in vivo.

    “treatment with either agonistic aCD40 mAbs or AZD5582 provided antitumor effects in vivo (Figure 7B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Combining anti-PD-1 with anti-CD40 controlled B16F10 tumor growth and increased survival compared to monotherapies.

    “We found that combining aPD-1 with aCD40 mAbs controlled B16F10 tumor growth (Figure S7E and F) and resulted in increased mouse survival (Figure 7D), when compared to aPD-1 or aCD40 monotherapies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    IL-12-positive dendritic cells express the highest amounts of CD80 and CD86, the costimulatory ligands for CD28.

    “since IL-12+ DCs express the highest levels of CD28’s co-stimulatory ligands, CD80 and CD86”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In the single-cell RNA sequencing, 4095 cells passed quality control and were sequenced.

    “In total, 4095 cells (1154 untreated and 2941 aPD-1 treated cells) passed QC and were sequenced.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    IFNG was not detectably increased in post-treatment samples, which is expected from tissue collection timing and rapid IFN-γ on/off cycling.

    “IFNG was not detectably increased in the post-treatment samples, which is expected from the timing of tissue collection and rapid on/off cycling of IFN-γ production by T cells (Slifka et al., 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Slifka et al., 1999 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Anti-PD-1 and anti-CD40 monotherapies incompletely controlled MC38 tumor growth, whereas the combination produced a complete, durable response in most animals.

    “We found that monotherapies incompletely controlled tumor growth, whereas the combination treatment produced a complete, durable response in most animals treated (Figure 7C and Figure S7B and C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Anti-PD-1 affects at least two non-overlapping tumor cell populations: CD8+ T cells that activate IFN-γ signaling and DC-like cells that turn on IL-12.

    “These findings indicate that aPD-1 delivery to tumors functionally impacts at least two non-overlapping cell populations, which respond differently to treatment: CD8+ T cells that activate the IFN- γ signaling pathway , and DC-like cells that turn on IL-12 production.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The difference in CD103 expression between MC38 and lung tumors may be due to tissue location.

    “This discrepancy may be due to tissue location, as we found that IL-12+ DCs expressed CD103 in lung tumor models (Figure S2D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The need for both T cell co-stimulation and IL-12 for maximal IFN-γ response likely reflects a requirement for CD28 to rescue exhausted CD8+ T cells and possibly PD-1 limiting CD28 co-stimulation.

    “The requirement for both T cell co-stimulation and IL-12 to achieve maximal IFN-γ response likely reflected the need of CD28 to rescue exhausted CD8+ T cells, and possibly also the role of PD-1 in limiting CD28-mediated co-stimulation (Kamphorst et al., 2017; Hui et al., 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kamphorst et al., 2017 source

      Not checked in the free run.

    • cites Hui et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Anti-PD-1 has an indirect effect on DCs that is mediated through IFN-γ and is critical for IL-12 induction and treatment response.

    “Together, we find an indirect aPD-1 effect on DCs; this effect was mediated through IFN-γ and is critical for IL-12 induction and, consequently , treatment response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Anti-PD-1 treatment induces IL-12 production by DCs, and both DCs and IL-12 critically regulate anti-PD-1 treatment potency.

    “Collectively , these data indicate that aPD-1 treatment induces IL-12 production by DCs, and that both DCs and IL-12 critically regulate aPD-1 treatment potency .”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The melanoma biopsy study from the ImmunoPulse IL-12 trial was approved by each participating organization's institutional review board.

    “All biopsies were from University of California, San Francisco Medical Center-Mt. Zion, San Francisco, and Huntsman Cancer Institute, Salt Lake City , Utah, and were approved by each organization’s institutional review board.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    IL-12 production required DC sensing of IFN-γ and licensed effector T cell responses in mice and cancer patients.

    “IL-12 production required DC sensing of IFN-γ , and, in turn, licensed effector T cell responses in both mice and cancer patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Intratumoral delivery of IL-12-encoding plasmids is safe and has shown antitumor efficacy as a single agent.

    “targeted intratumoral delivery of IL-12 encoding plasmids is safe and has already demonstrated antitumor efficacy as monotherapy (Daud et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Daud et al., 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Starting tumor volumes were normalized across treatment groups.

    “starting tumor volumes were normalized between treatment groups.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Responses to immunotherapy can be improved through rational drug combinations that accentuate crosstalk between lymphoid and myeloid immune compartments.

    “We suggest further that responses to immunotherapy can be improved through rational drug combinations that accentuate the crosstalk between lymphoid and myeloid immune compartments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dendritic cells play a critical role in priming T cells within lymph nodes.

    “besides their critical role for priming T cells in lymph nodes (Martin-Fontecha et al., 2003)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Martin-Fontecha et al., 2003 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    IL-12 may serve as both a marker and a functional property of immunostimulatory tumor dendritic cells.

    “IL-12 may be both a marker and functional feature of immunostimulatory tumor DCs, based on our findings that i) IL-12+ DCs share many features with cross-presenting DC1 cells, including expression of Batf3, Irf8, Flt3, and Ly 75 (DEC205), and ii) IL-12 is required for immunotherapy efficacy”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Distribution and effector functions of antibodies may differ between species and antibody compositions.

    “Caveats still exist with this imaging approach however as distribution and effector functions of antibodies may differ between species and antibody compositions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The Basel human tumor study was approved by the local ethical review board.

    “The study was approved by the local Ethical Review Board (Ethikkommission Nordwestschweiz) and University Hospital Basel, Switzerland.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The data link the non-canonical NFkB pathway to antitumor intratumoral DCs and to anti-PD-1 treatment efficacy, and indicate that targeting non-canonical NFkB components can be therapeutic in cancer.

    “Taken together, these data linked the non-canonical NFkB pathway to antitumor intratumoral DCs and to aPD-1 treatment efficacy , and indicated that targeting non-canonical NFkB components can be therapeutic in cancer.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Study design and conductown data

    Blood from FTY720-treated mice was used to confirm defects in lymphocyte trafficking.

    “Blood from mice was used to confirm lymphocyte trafficking defects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Antitumor immune functions may not necessarily be cell type-dependent.

    “antitumor immune functions may not necessarily be cell type-dependent”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    DC targeting can augment immunotherapy efficacy and sensitize tumors to anti-PD-1 treatment in an IL-12-dependent manner.

    “These data indicate that DC targeting can augment immunotherapy efficacy and sensitize tumors to aPD-1 treatment in an IL-12-dependent manner.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    All patients in the Basel study gave written consent for analysis of their tumor samples.

    “All patients consented in writing to the analysis of their tumor samples.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Under different experimental contexts, NK cells may also produce IFN-γ and macrophages may also produce IL-12.

    “under different experimental contexts it is possible that NK cells may also produce IFN-γ and macrophages may also produce IL-12.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The current study's results support the idea that dendritic cells within tumors can perform important antitumor functions and can promote anti-PD-1 immunotherapy.

    “The findings presented here align with the notion that intratumoral DCs can exhibit key antitumor functions and promote aPD-1 immunotherapy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Mouse tumors were allowed to reach a maximum diameter of 2 cm or to ulcerate, and these conditions were used as survival-study endpoints under MGH IACUC rules.

    “Mouse tumors were allowed to grow to a maximum of 2 cm in diameter, or until tumor ulceration occurred. These were considered as endpoints for survival experiments in accordance with MGH IACUC regulations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Combinations of CD40 agonists with PD-1 pathway inhibitors and of cIAP inhibitors with anti-PD-L1 are currently being tested in clinical trials.

    “Treatments combining CD40 agonists with PD-1 pathway inhibitors (NCT03123783, NCT02376699), and cIAP inhibitors with aPD-L1 (NCT03270176), are currently in clinical trials.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites NCT03123783

      Not checked in the free run.

    • cites NCT02376699

      Not checked in the free run.

    • cites NCT03270176

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both the CD40 agonist/PD-1 inhibitor and cIAP inhibitor/anti-PD-L1 strategies may depend on the non-canonical NFkB pathway and dendritic cells.

    “We suggest that both treatment strategies may rely upon the non-canonical NFkB pathway and DCs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    IL-12-producing DCs were enriched for non-canonical NFkB signaling components; NIK was required for anti-PD-1 response; agonism of non-canonical NFkB produced an IL-12-dependent antitumor response.

    “We also showed that IL-12-producing DCs were enriched for non-canonical NFkB signaling pathway components, that the critical non-canonical NFkB kinase NIK was required for aPD-1 response, and that agonism of the non-canonical NFkB pathway in a therapeutic setting produced an IL-12-dependent antitumor response.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cross-presenting tumor dendritic cells have increased IL-12 expression.

    “prior evidence that cross- presenting tumor DCs have elevated IL-12 expression (Broz et al., 2014; Ruffell et al., 2014)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Broz et al., 2014 source

      Not checked in the free run.

    • cites Ruffell et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The cDC1 subset of dendritic cells is skilled at cross-presenting antigens.

    “the cDC1 subtype of DCs, which resembles the DC1 subtype presented here, is adept at cross- presenting antigens (Schlitzer and Ginhoux, 2014)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schlitzer and Ginhoux, 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dendritic cells occur inside tumors, where they attract T cells and locally stimulate responses against tumor antigens.

    “recent studies demonstrated that DCs can be found in tumors, where they recruit T cells and stimulate tumor-reactive T cell responses locally (Spranger et al., 2014; de Mingo Pulido et al., 2018)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Spranger et al., 2014 source

      Not checked in the free run.

    • cites de Mingo Pulido et al., 2018 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Real-time in vivo imaging can identify primary targets of immunotherapeutics and how the tumor microenvironment responds to treatment.

    “Real-time in vivo imaging allows one to identify not only primary targets of immunotherapeutics (drug pharmacokinetics) (Arlauckas et al., 2017) but also how the tumor microenvironment responds to treatment (drug pharmacody namics).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Arlauckas et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Anti-PD-1 directly induced IFN-γ production by activated T cells but indirectly induced IL-12 production by a subset of intratumoral DCs.

    “Principally , we identified that aPD-1 directly induced IFN-γ production by activated T cells, but indirectly induced IL-12 production by a subset of intratumoral DCs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Animal experiments were approved by the MGH Institutional Animal Care and Use Committee and followed its regulations.

    “Experiments were approved by the MGH Institutional Animal Care and Use Committee (IACUC) and were performed in accordance with MGH IACUC regulations.”
    Quote in the paperNot a substantial claim
47 of 47

  • The paper relies on this without support.

    B cell depletion did not affect anti-CD40 therapy in this experimental model.

    “We found that B cell depletion had no effect on aCD40 therapy , suggesting that B cells are not necessary for aCD40 treatment in this experimental model (data not shown).”

  • The paper relies on this without support.

    The MC38 tumor model responds to anti-PD-1 treatment.

    “Here, we initially used the MC38 mouse tumor model because it is sensitive to aPD-1 treatment and thus is relevant to define mechanisms dictating treatment success.”
2 of 2

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?

  • IFN-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).”

    From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [91]

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Authors
Garris, C. S., Arlauckas, S. P., Kohler, R. H., Trefny, M. P., Garren, S., Piot, C., Engblom, C., Pfirschke, C., Siwicki, M., Gungabeesoon, J., Freeman, G. J., Warren, S. E., Ong, S., Browning, E., Twitty, C. G., Pierce, R. H., Le, M. H., Algazi, A. P., Daud, A. I., Pai, S. I., Zippelius, A., Weissleder, R., & Pittet, M. J.
Affiliations
  • Harvard University (US)
  • Massachusetts General Hospital (US)
  • University Hospital of Basel (CH)
  • Nanostring Technologies (United States) (US)
  • University of California, San Francisco (US)
ORCID
Venue
Immunity
Publisher
Elsevier BV
Published
2018-12
Volume
49
Issue
6
Pages
1148-1161.e7
ISSN
1074-7613 (ISSN-L)
DOI
10.1016/j.immuni.2018.09.024
PMC
PMC6301092
OpenAlex
W2904099327
Semantic Scholar
1209b0cd82a4fa3c176fbcbc8f01817d21cdace6
Cited by
966
References
62
Citations by year
2026: 101 · 2025: 118 · 2024: 130 · 2023: 138 · 2022: 146 · 2021: 150 · 2020: 124 · 2019: 57 · 2018: 1 · 2012: 1
FWCI
30.99
Type
journal article
Language
en
Update notices
erratum (2022-09-13)
Open access
Licence
Locations
  • Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • Archive ouverte UNIGE (University of Geneva) (acceptedVersion, other-oa)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders
  • Samana Cay MGH Research Scholar Fund
  • Robert Wenner Award from the Swiss Cancer League
  • NIH (R01-AI084880, R01-CA218579, R01-AI123349, R01-CA206890, R33-CA202064, U01CA206997, P01 AI056299, P50CA101942, F31-CA196035, T32-CA79443)
  • Swiss National Cancer Foundation (320030_162575)
  • MGH ECOR Tosteson Postdoctoral Fellowship
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
anti-PD-1 therapy, immune checkpoint blockade, tumor-infiltrating dendritic cells, IL-12, interferon-gamma, T cell-mediated antitumor immunity, NF-κB signaling, intravital imaging, single-cell RNA sequencing, pharmacodynamics, cancer immunotherapy
MeSH terms
Adult, Aged, Aged, 80 and over, Animals, Antibodies, Monoclonal, Dendritic Cells, Female, Humans, Immunotherapy, Interferon-gamma, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Neoplasms, T-Lymphocytes, Signal Transduction, NF-kappa B, Interleukin-12, Programmed Cell Death 1 Receptor

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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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