The DOI matches its Crossref record; 61 of the 62 references it cites were found in a registry or an index; none of the 21 sources its claims cite is checked for support yet.
Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12
Open accessAbstract
&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.
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61 Own result · 36 Own interpretation · 15 Not checked yet · 7 Own method · 1 No basis given
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“Stimulated CD8+ T cells substantially increased IFN-γ production in the presence of IL-12 (Figure 4C)”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > IL-12 activates tumor-infiltrating lymphocyte effector functions in mice
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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)”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > IL-12 activates tumor-infiltrating lymphocyte effector functions in mice
plain- Asserted: passes — The authors put it forward as true.
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“Flow cytometry analysis confirmed these cells to be MHC class II+ F4/80– (Figure S1D)”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > scRNAseq shows DC-restricted IL-12 production
plain- Asserted: passes — The authors put it forward as true.
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“IL-12p40-eYFP+ cells displayed a branched morphology (mean circularity index: 0.54 ± 0.4), suggesting they were DCs.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > Successful aPD-1 treatment triggers endogenous IFN-γ and IL-12 responses within tumors
hedged- Asserted: passes — The authors put it forward as true.
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“parabiosis of tumor-bearing mice indicated that these cells could derive from a blood circulating precursor (Figure S1E).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > scRNAseq shows DC-restricted IL-12 production
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In the paper
“We found that intratumoral IL-12 substantially expanded IFN-γ-eYFP+ cells (5.9 ± 0.7 fold increase by day four; Figure 4A).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > IL-12 activates tumor-infiltrating lymphocyte effector functions in mice
plaindirect- Asserted: passes — The authors put it forward as true.
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“scRNAseq data indicated that aPD-1 treatment triggered the proliferation of tumor-infiltrating CD8+ T cells (Figure S4C).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > IL-12 activates tumor-infiltrating lymphocyte effector functions in mice
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“and were unresponsive to aPD-1 treatment (Figure 3F)”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > IFN-γ sensing by DCs controls IL-12 production
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“blocking lymphocyte recirculation through treatment with the trafficking inhibitor FTY 720 did not affect the antitumor response to aPD-1 treatment (Figure S4D and E).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > IL-12 activates tumor-infiltrating lymphocyte effector functions in mice
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“we found that IL-12+ DCs expressed CD103 in lung tumor models (Figure S2D).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > scRNAseq shows DC-restricted IL-12 production
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 32
- Probably not a substantial claim. 21
- The quote only partly states this claim. 1
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In the paper
“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).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > Successful aPD-1 treatment triggers endogenous IFN-γ and IL-12 responses within tumors
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > Successful aPD-1 treatment triggers endogenous IFN-γ and IL-12 responses within tumors
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > scRNAseq shows DC-restricted IL-12 production
What the sources say
- Not checked yetcites Broz et al., 2014 source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“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).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > scRNAseq shows DC-restricted IL-12 production
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and DC1s and DC2s expressed distinct chemokines and chemokine receptors (Figure 2E).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > scRNAseq shows DC-restricted IL-12 production
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Decreased IL-12 production by DCs (Figure S3D) and decreased numbers of IL-12+ DCs (Figure S3E, F) both contributed to this reduction.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > IFN-γ sensing by DCs controls IL-12 production
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > Successful aPD-1 treatment triggers endogenous IFN-γ and IL-12 responses within tumors
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > scRNAseq shows DC-restricted IL-12 production
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“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”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > Activation of the non-canonical NFkB pathway amplifies IL-12-producing DCs
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“treatment with either agonistic aCD40 mAbs or AZD5582 provided antitumor effects in vivo (Figure 7B).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > Amplification of IL-12+ DCs improves cancer immunotherapy in an IL-12-dependent manner
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > Amplification of IL-12+ DCs improves cancer immunotherapy in an IL-12-dependent manner
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“since IL-12+ DCs express the highest levels of CD28’s co-stimulatory ligands, CD80 and CD86”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In total, 4095 cells (1154 untreated and 2941 aPD-1 treated cells) passed QC and were sequenced.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > METHOD DETAILS > Single Cell RNA Sequencing
plainn = 4,095- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > IL-12 activates tumor-infiltrating lymphocyte effector functions in cancer patients
What the sources say
- Not checked yetcites Slifka et al., 1999 source
plainn = 19- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > Amplification of IL-12+ DCs improves cancer immunotherapy in an IL-12-dependent manner
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > Successful aPD-1 treatment triggers endogenous IFN-γ and IL-12 responses within tumors
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This discrepancy may be due to tissue location, as we found that IL-12+ DCs expressed CD103 in lung tumor models (Figure S2D).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > scRNAseq shows DC-restricted IL-12 production
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > IL-12 activates tumor-infiltrating lymphocyte effector functions in mice
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > IFN-γ sensing by DCs controls IL-12 production
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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 .”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > DCs and IL-12 are relevant to aPD-1 therapy
hedgeddirect- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plainn = 19- Asserted: passes — The authors put it forward as true.
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In the paper
“IL-12 production required DC sensing of IFN-γ , and, in turn, licensed effector T cell responses in both mice and cancer patients.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“targeted intratumoral delivery of IL-12 encoding plasmids is safe and has already demonstrated antitumor efficacy as monotherapy (Daud et al., 2008).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
What the sources say
- Not checked yetcites Daud et al., 2008 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“starting tumor volumes were normalized between treatment groups.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We suggest further that responses to immunotherapy can be improved through rational drug combinations that accentuate the crosstalk between lymphoid and myeloid immune compartments.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“besides their critical role for priming T cells in lymph nodes (Martin-Fontecha et al., 2003)”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
What the sources say
- Not checked yetcites Martin-Fontecha et al., 2003 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Caveats still exist with this imaging approach however as distribution and effector functions of antibodies may differ between species and antibody compositions.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The study was approved by the local Ethical Review Board (Ethikkommission Nordwestschweiz) and University Hospital Basel, Switzerland.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > Amplification of IL-12+ DCs improves cancer immunotherapy in an IL-12-dependent manner
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Blood from mice was used to confirm lymphocyte trafficking defects.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > METHOD DETAILS > FTY 720 Treatments
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“antitumor immune functions may not necessarily be cell type-dependent”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data indicate that DC targeting can augment immunotherapy efficacy and sensitize tumors to aPD-1 treatment in an IL-12-dependent manner.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Results > Amplification of IL-12+ DCs improves cancer immunotherapy in an IL-12-dependent manner
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All patients consented in writing to the analysis of their tumor samples.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plainn = 6- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“under different experimental contexts it is possible that NK cells may also produce IFN-γ and macrophages may also produce IL-12.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The findings presented here align with the notion that intratumoral DCs can exhibit key antitumor functions and promote aPD-1 immunotherapy.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Treatments combining CD40 agonists with PD-1 pathway inhibitors (NCT03123783, NCT02376699), and cIAP inhibitors with aPD-L1 (NCT03270176), are currently in clinical trials.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
What the sources say
- Not checked yetcites NCT03123783
- Not checked yetcites NCT02376699
- Not checked yetcites NCT03270176
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We suggest that both treatment strategies may rely upon the non-canonical NFkB pathway and DCs.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“prior evidence that cross- presenting tumor DCs have elevated IL-12 expression (Broz et al., 2014; Ruffell et al., 2014)”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the cDC1 subtype of DCs, which resembles the DC1 subtype presented here, is adept at cross- presenting antigens (Schlitzer and Ginhoux, 2014)”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
What the sources say
- Not checked yetcites Schlitzer and Ginhoux, 2014
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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)”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
What the sources say
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
What the sources say
- Not checked yetcites Arlauckas et al., 2017 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Experiments were approved by the MGH Institutional Animal Care and Use Committee (IACUC) and were performed in accordance with MGH IACUC regulations.”
§ Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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.”
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?
In the citing paper
“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]
Citations
Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628 · cited 1×
“Immune checkpoint blockade has emerged as a critical treatment against various cancer types (Topalian et al., 2012).”
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 · cited 1×
“, 2017), neoantigen abundance (Rizvi et al., 2015), MHC class I expression (Marty et al.”
Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets.
Macosko, E. Z., Basu, A., Satija, R., Nemesh, J., Shekhar, K., Goldman, M., Tirosh, I., Bialas, A. R., Kamitaki, N., Martersteck, E. M., et al. (2015) · Cell · doi:10.1016/j.cell.2015.05.002 · Cited by 7,110 · cited 1×
“All cells (n = 4,095) were clustered into unbiased cell type classifications using the Seurat single-cell analysis R package (Macosko et al., 2015).”
Spatial reconstruction of single-cell gene expression data
Satija, R., Farrell, J. A., Gennert, D., Schier, A. F., & Regev, A. (2015) · Nature Biotechnology · doi:10.1038/nbt.3192 · Cited by 7,055 · cited 3×
“REAGENT or RESOURCE SOURCE IDENTIFIER Software and Algorithms Seurat R Package (Satija et al., 2015) https://satijalab.org/seurat/; RRID: SCR_016341 FIJI ImageJ Version 1.51s FIJI https://fiji.sc; RRID: SCR_002285 SPRING (Weinreb et al., 2017) https://kleintools.hms.harvard.edu/tools/ spring.html FlowJo v.10.4 FlowJo,…”
InfluentialCancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion
Schreiber, R. D., Old, L. J., & Smyth, M. J. (2011) · Science · doi:10.1126/science.1203486 · Cited by 6,474 · cited 1×
“, 2017), interferon-g (IFN-g) production (Schreiber et al., 2011; Ayers et al., 2017), neoantigen abundance (Rizvi et al.”
Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors
Routy, B., Le Chatelier, E., Derosa, L., Duong, C. P. M., Alou, M. T., Daillère, R., Fluckiger, A., Messaoudene, M., Rauber, C., Roberti, M. P., et al. (2018) · Science · doi:10.1126/science.aan3706 · Cited by 5,671 · cited 1×
“, 2017), patient microbiota (Matson et al., 2018; Routy et al., 2018), and antibody composition (Arlauckas et al.”
PD-1 and Its Ligands in Tolerance and Immunity
Keir, M. E., Butte, M. J., Freeman, G. J., & Sharpe, A. H. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.26.021607.090331 · Cited by 5,378 · cited 1×
“These inhibitory pathways are important because they protect the host from uncontrolled immune activation (Keir et al., 2008) but they can also be co-opted by tumors, which make them resist immune attack (Wherry, 2011).”
Self-citationWherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062 · cited 2×
“, 2008) but they can also be co-opted by tumors, which make them resist immune attack (Wherry, 2011).”
Molecular and genetic properties of tumors associated with local immune cytolytic activity
Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G., & Hacohen, N. (2015) · Cell · doi:10.1016/j.cell.2014.12.033 · Cited by 3,825 · cited 2×
“Comparison of pre- and post-treatment samples revealed that IL-12 delivery enhanced expression of core cytolytic genes (Rooney et al., 2015) within tumors (Figures 5A and 5B).”
Cited by
Sorted by citations
Bagchi, S., Yuan, R., & Engleman, E. G. (2021) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-042020-042741 · Cited by 2,189
NF-κB in biology and targeted therapy: new insights and translational implications
Guo, Q., Jin, Y., Chen, X., Ye, X., Shen, X., Lin, M., Zeng, C., Zhou, T., & Zhang, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01757-9 · Cited by 2,405
“533 The upregulation of alternative NF-κ B pathway in tumor-in fi ltrating DCs can be induced by anti-PD-1 treatment, leading to subsequent secretion of IL-12, which enhanced CD8 + T cell antitumor activity.”
BackgroundSaxena, M., van der Burg, S. H., Melief, C. J. M., & Bhardwaj, N. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00346-0 · Cited by 1,581
Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion
Jhunjhunwala, S., Hammer, C., & Delamarre, L. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00339-z · Cited by 1,570
Žilionis, R., Engblom, C., Pfirschke, C., Savova, V., Zemmour, D., Saatcioglu, H. D., Krishnan, I., Maroni, G., Meyerovitz, C. V., Kerwin, C. M., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.009 · Cited by 1,486
“, 2016) but some of these cells can remain within tumors (Garris et al. 2018).”
BackgroundMethodInfluentialSelf-citation
Metadata
- 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)
- 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
- FWCI
- 30.99
- Type
- journal article
- Language
- en
- Update notices
- erratum (2022-09-13)
- Open access
- bronze
- doi.org
- 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
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.
A language model drew the claims from the paper on 2026-10-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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