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Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues
Open accessAbstract
A combination of anti-CTLA-4 plus anti-PD-1/PD-L1 is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAEs). Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrating myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFN-γ-dependent mechanism. Targeting the HIF-1α/PD-L1 axis in tumor cells reactivated tumor-infiltrating lymphocytes and caused tumor rejection. The HIF-1α inhibitor echinomycin potentiated the cancer immunotherapeutic effects of anti-CTLA-4 therapy, with efficacy comparable to that of anti-CTLA-4 plus anti-PD-1 antibodies. However, while anti-PD-1 exacerbated irAEs triggered by ipilimumab, echinomycin protected mice against irAEs by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1/PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment to achieve safer and more effective immunotherapy.
Overview
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TL;DR
Targeting HIF-1α with liposomal echinomycin (LEM) suppresses PD-L1 in the tumor microenvironment and reactivates antitumor immunity, while unexpectedly inducing PD-L1 in normal tissues via IFN-γ. This differential regulation potentiates anti–CTLA-4 therapy without the irAE exacerbation seen with anti–PD-1.
Key findings
- LEM reduced PD-L1 on tumor cells and tumor-infiltrating myeloid cells (M-MDSCs, PMN-MDSCs, and CD11b+CD11c+ cells, ~90% of which were F4/80+ TAMs), increased IFN-γ+CD8+ (Tc1) and IFN-γ+CD4+ (Th1) TILs, and inhibited tumor growth in immunocompetent but less so in immunodeficient mice.
- LEM potentiated anti–CTLA-4 (9D9) therapy in 4T1, E0771, and MC38 models, with efficacy comparable to anti–CTLA-4 plus anti–PD-1; optimal efficacy required CD8+, NK, and CD4+ cells, with CD8+ cells most critical.
- In normal tissues, LEM induced PD-L1 in liver, kidney, and intestine by an IFN-γ–dependent mechanism; in CTLA4h/h-KI mice, LEM protected against ipilimumab-induced intestinal leakage, and adding anti–IFN-γ increased the frequency of mice with leakage from 7.7% to 20.0%.
- Anti–PD-1 abrogated LEM’s protection against ipilimumab-induced GI irAEs, whereas LEM protected mice by increasing normal-tissue PD-L1; the paper notes dual checkpoint blockade causes severe irAEs in 50%–90% of patients depending on setting.
Methods
- Syngeneic mouse tumor models: 4T1 and E0771 breast cancer and MC38 colon adenocarcinoma in BALB/c, C57BL/6, and NSG mice; genetic tools included shHif1a, shPdl1, and conditional Hif1a knockout in T cells.
- Treatments: liposomal echinomycin (LEM) i.v. at 0.15–0.25 mg/kg; anti–mouse CTLA-4 (9D9), anti–PD-1 (RMP1-14), anti–IFN-γ (XMG1.2), and depleting CD4/CD8/NK antibodies; readouts included flow cytometry, immunofluorescence, histology, and FITC-dextran intestinal permeability.
- GI irAE model: 10-day-old human CTLA4-knockin mice received ipilimumab i.p. on days 10, 13, 16, and 19; FITC-dextran assay on day 32. Statistics used t tests, 1-way/2-way ANOVA with Sidak’s post hoc test, and Pearson correlation in Prism 8, with P < 0.05 significant.
Limitations
- Stated: adult tumor-bearing mice tolerated high-dose anti–CTLA-4 without significant irAEs, so the irAE studies relied on young CTLA4h/h-KI mice.
- Stated: it is unclear whether LEM promotes Tc1 expansion in vivo by cell-intrinsic HIF-1α targeting or indirectly by reducing regulatory T cells.
- Evident: all efficacy and toxicity data are preclinical mouse models; no human clinical outcomes or patient data are reported.
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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
“In a second breast cancer model, E0771, the therapeutic effects of LEM were also more pronounced in immune-competent mice (Figure 2C).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Immunotherapeutic effect of LEM.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“LEM significantly inhibited 4T1 growth in both immunocompetent (BALB/c) and immunodeficient (NSG) recipients compared with each strain’s respective vehicle control (Figure 2B).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Immunotherapeutic effect of LEM.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“LEM did not further suppress sh-Pdl1 E0771 tumor growth in C57BL/6 (Figure 3C) or NSG (Figure 3D) recipients.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 in tumor cells by targeting the HIF-1α/PD-L1 axis.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“there was a marked reduction in PD-L1 expression in the tumors of LEM-treated mice.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Targeting HIF-1α suppresses PD-L1 expression in the TME.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“LEM more effectively inhibited sh-Scr E0771 tumor growth in C57BL/6 (Figure 3C) compared with NSG (Figure 3D) recipients”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 in tumor cells by targeting the HIF-1α/PD-L1 axis.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Under basal conditions, we found that knockdown of Hif1a reduced PD-L1 protein expression (Figure 1, G–J).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Targeting HIF-1α suppresses PD-L1 expression in the TME.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Both cell lines expressed HIF-1α and PD-L1 protein (Figure 1, A and B; see complete unedited blots in the supplemental material)”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Targeting HIF-1α suppresses PD-L1 expression in the TME.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“4T1 growth was more significantly inhibited in immunocompetent mice than in immunodeficient mice”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Immunotherapeutic effect of LEM.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“As with E0771, all therapeutic effects required immune competence (Figure 2D).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Immunotherapeutic effect of LEM.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“In C57BL/6, but not NSG recipients, genetic depletion of Hif1a (sh-Hif1a) in E0771 cells significantly inhibited tumor growth compared with E0771 transduced with scrambled shRNA (sh-Scr) in mice of the same respective strains (Figure 3B).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 in tumor cells by targeting the HIF-1α/PD-L1 axis.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“a reduction in PD-L1 protein was observed in cells treated with the HIF-1α inhibitor echinomycin (Figure 1B).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Targeting HIF-1α suppresses PD-L1 expression in the TME.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“LEM did not inhibit sh-Hif1a E0771 tumor growth, regardless of the recipient strain (Figure 3, C and D).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 in tumor cells by targeting the HIF-1α/PD-L1 axis.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“knockdown of Hif1a abrogated the ability of echinomycin to decrease PD-L1 protein (Figure 1, H–J).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Targeting HIF-1α suppresses PD-L1 expression in the TME.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“the tumor growth rates of E0771 with Hif1a knockdown were also significantly reduced in immunocompetent versus immunodeficient recipients (Figure 3B).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 in tumor cells by targeting the HIF-1α/PD-L1 axis.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“treatment of E0771 cells with the hypoxia mimetic CoCl2 further upregulated PD-L1 from the basal levels seen in normoxia (Figure 1C).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Targeting HIF-1α suppresses PD-L1 expression in the TME.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“PD-L1 expression was associated with EGFP reporter activity in the tumor cells (Figure 1E).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Targeting HIF-1α suppresses PD-L1 expression in the TME.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“we performed similar drug-treatment experiments using immunocompetent C57BL/6 recipients and the E0771 breast cancer (Figure 4C) or MC38 colon adenocarcinoma (Figure 4D) model and observed synergistic effects in all models.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > HIF-1α inhibition potentiates anti–CTLA-4 immunotherapy.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“In response to CoCl2 stimulation, the resultant 4T1-HRE-EGFP cells exhibited a marked increase in EGFP reporter fluorescence (Figure 1D).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Targeting HIF-1α suppresses PD-L1 expression in the TME.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“anti–mouse CTLA-4 mAb (9D9) in combination with LEM significantly inhibited 4T1 tumor growth more effectively than either monotherapy alone.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > HIF-1α inhibition potentiates anti–CTLA-4 immunotherapy.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“The same was seen for PD-1 expression on CD4+ TILs (Figure 6B)”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“in all treated groups, the mean frequencies of CD4+ TILs expressing perforin were roughly double that of the control group (Figure 6H).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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 T cell accumulation (Figure 8C) in the intestines.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Higher expression of cytolytic effector molecules granzyme B and perforin were noted in CD8+ TILs of 9D9 plus LEM–treated mice versus vehicle (Figure 6, E and F).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“T cell infiltration was reduced in 9D9 plus LEM–treated mice when compared with 9D9 alone (Figure 7, B–D).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“While LEM did not significantly impact the frequencies of tumor-infiltrating lymphocyte (TIL) or tumor-infiltrating myeloid subsets”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“ipilimumab treatment resulted in elevated PD-L1 expression (Figure 8B)”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“PD-L1 expression in these tissues was elevated in mice treated with 9D9 (Figure 7A).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 the protective effect of LEM depends on IFN-γ because the effect was abolished by the anti–IFN-γ mAb XMG1.2 (Figure 8F).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Loss of Hif1a did not significantly impact the proportion of CD4+ and CD8+ TILs expressing IFN-γ, T-bet, or RORγt, or the frequencies of Tregs or Th17 cells.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“knockdown of Pdl1 in the tumor cells significantly increased the frequencies of Tc1 and Th1 cells, phenocopying the effects of LEM (Supplemental Figure 8).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“LEM protected against ipilimumab-induced intestinal leakage by a PD-L1–dependent mechanism, as this protection was abrogated by anti–PD-1 (Figure 8E).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 to a lesser extent, for CTLA-4 expression on CD8+ TILs (Supplemental Figure 5A).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“LEM protected against ipilimumab-induced intestinal leakage by a PD-L1–dependent mechanism, as this protection was abrogated by anti–PD-1 (Figure 8E).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“We observed that mice with high levels of intestinal PD-L1 had much lower intestinal permeability (Figure 8D).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“These data showed that the protective effect of LEM is abrogated by the anti–PD-1 mAb (Figure 8F).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“LEM significantly reduced PD-L1 expression on tumor cells (Figure 5A)”
- Also stated in: § Abstract · plain
“Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrating myeloid cells”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · plain
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
“Granzyme B and perforin in CD8+ TILs was slightly reduced in Hif1a-KO mice, but not significantly.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“Consistent with the FITC-dextran data in Figure 8E, ipilimumab induced intestinal inflammation (see Supplemental Figure 16 for additional information).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“The absolute numbers of Tc1 and Th1 cells were also highest in 9D9 plus LEM–treated mice, as shown in Supplemental Figure 3.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“LEM enhanced PD-L1 expression in the intestine compared with ipilimumab alone (Figure 8G).”
- Also stated in: § LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice. · boosted
“The elevated PD-L1 expression was confirmed by flow cytometry using digested intestinal tissues (Figure 8H).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice. · boosted
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
“When 9D9 was combined with anti–PD-1 (RMP1-14), the mice had high T cell infiltration in liver and kidney (Figure 7, B–D).”
- Also stated in: § Abstract · plain
“while anti–PD-1 exacerbated irAEs triggered by ipilimumab”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · plain
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
“9D9 reduced the frequencies of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs)”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“we also noted increased MHCII expression in 9D9 plus LEM–treated versus vehicle-treated mice (Supplemental Figure 4).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“The frequencies of T cells in the spleen, including Tc1 and Th1, were comparable when either anti–PD-1 or LEM was used in conjunction with anti–CTLA-4 mAb (Figure 7, E–G).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“the adult mouse tolerated a high dose of anti–CTLA-4 antibody without significant irAEs (Supplemental Figure 15).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“LEM significantly reduced PD-L1 expression on tumor cells (Figure 5A), and tumor-infiltrating monocytic MDSCs (M-MDSCs) (Figure 5B), PMN-MDSCs (Figure 5C), and CD11b+CD11c+ double-positive cells (Figure 5D), with or without anti–CTLA-4 therapy.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“but only 9D9 resulted in hepatic and renal infiltration of T cells (Figure 7, B–D).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“The proportions of CD8+ and CD4 +TILs expressing RORγt were unchanged among different groups (Supplemental Figure 5, G and H).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“we noted an increase in CD3+ TIL infiltration into hypoxic areas of the tumors in LEM-treated mice (Supplemental Figure 10).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Notably, inhibition of PD-L1 on tumor cells by LEM was preserved in mice with conditional knockout of Hif1a in T cells.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Interestingly, LEM also induced PD-L1 (Figure 7A)”
- Also stated in: § Abstract · plain
“but unexpectedly induced PD-L1 in normal tissues by an IFN-γ–dependent mechanism”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · plain
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
“Moreover, IFN-γ was increased in intestines from mice that received treatment with both LEM and ipilimumab (Supplemental Figure 17)”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Moreover, in mice that received ipilimumab plus LEM treatment, the addition of anti–IFN-γ mAb increased the frequency of mice with intestinal leakage from 7.7% to 20.0% (Figure 8E).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“most of the CD11b+CD11c+ cells were tumor-associated macrophages (TAMs), as roughly 90% expressed F4/80”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“The proportions of CD8+ and CD4+ TILs expressing T-bet were significantly increased in 9D9 plus LEM–treated mice versus vehicle (Supplemental Figure 5, C and D).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“In CD4+, but not CD8+ TILs, we found an increased frequency of PD-1+ cells (Supplemental Figure 7).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“Our data presented herein show a strong effect of LEM in inducing IFN-γ–producing cells, including Tc1 and Th1 cells.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Surprisingly, LEM induced PD-L1 expression in normal tissues of immunocompetent mice, including liver, kidney, and colon.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Thus, pharmacologic or genetic targeting of HIF-1α in tumor cells alone can confer an immunotherapeutic effect.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 in tumor cells by targeting the HIF-1α/PD-L1 axis.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 data support the conclusion that echinomycin confers immunotherapeutic effects in vivo by targeting the HIF-1α/PD-L1 axis in tumor cells.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 in tumor cells by targeting the HIF-1α/PD-L1 axis.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 loss of biological activity of echinomycin following knockdown of Hif1a in E0771 provides genetic evidence that echinomycin confers an immunotherapeutic effect in vivo by targeting the HIF-1α in tumor cells.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 in tumor cells by targeting the HIF-1α/PD-L1 axis.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 results provide evidence that HIF-1α is involved in coordinating PD-L1 expression on tumor-infiltrating myeloid cells in the TME.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“XMG1.2 also abrogated PD-L1 expression in the kidney and liver in the absence of 9D9, indicating that IFN-γ is responsible for PD-L1 induction by LEM in these tissues (Supplemental Figure 13).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 demonstrated that the therapeutic effect of blocking the PD-1–PD-L1 interaction can be similarly achieved by either anti–PD-1 or echinomycin.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > HIF-1α inhibition potentiates anti–CTLA-4 immunotherapy.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 the decreased PD-L1 expression is not due to a T cell–intrinsic effect of echinomycin (Supplemental Figure 9).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Therefore, suppression of PD-L1 on tumor cells can at least partially account for the enhanced CD8+ TIL function and therapeutic effects provided by LEM in the immune-competent mouse.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 current study supports echinomycin’s reemergence as an immunotherapeutic agent.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Clinical development of echinomycin for solid tumors has met with minimal success.
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
“cleaved caspase 3 staining suggested that the induced PD-L1 regulates T infiltration by triggering apoptosis (Figure 7H).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 association between intestinal permeability and PD-L1 expression supports the hypothesis that ipilimumab-induced PD-L1 serves as a limiting factor against ipilimumab-induced GI irAEs.”
- Also stated in: § Abstract · plain
“echinomycin protected mice against irAEs by increasing PD-L1 levels in normal tissues”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · plain
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
“they allow us to propose what we believe is a new paradigm: exploiting differential regulatory pathways of PD-L1 expression simultaneously can uncouple immunotherapeutic effects and irAEs.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The current approach that overcomes tumor evasion of host immunity also disables the immune tolerance checkpoint, leading to significant irAEs, particularly when used in conjunction with anti–CTLA-4 antibodies.
In the paper
“human CTLA4–knockin (CTLA4h/h-KI) mice, which are susceptible to irAE induction by ipilimumab at a young age (30).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
What the sources say
- Not checked yetcites [30] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Therefore, abrogating HIF-1α–mediated immune suppression in tumor cells and tumor-associated myeloid cells may be more important for immunotherapeutic efficacy than preserving HIF-1α function in T cells.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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, the data suggested that through induction of IFN-γ, echinomycin confers protection against ipilimumab-induced GI irAEs by elevating PD-L1 expression to fortify the PD-1–PD-L1 checkpoint.”
- Also stated in: § LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice. · hedged
“These data suggested that the IFN-γ/PD-L1 axis is responsible for the echinomycin-mediated protection against ipilimumab-induced GI irAEs.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice. · hedged
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
“Thus, the reductions in T cells in liver and kidney induced by LEM were not the result of general T cell inactivation.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“In this study, we demonstrate that targeting HIF-1α can achieve such an effect in preclinical models of cancer.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“In our studies of breast cancer, we found that reformulating echinomycin with liposomes (LEM) enabled potent therapeutic effects in orthotopic xenograft mouse models of triple-negative breast cancer, including primary tumor growth and metastasis in the MDA-MB-231 and SUM-159 models (35).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
What the sources say
- Not checked yetcites [35] Bailey, 2020, Liposomal formulation of HIF-1α inhibitor echinomycin eliminates established metastases of triple-negative breast cancer, Nanomedicine
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Palazon et al. showed that selective HIF-1α targeting in T cells inhibited IFN-γ and granzyme B production in CD8+ TILs (43).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
What the sources say
- Not checked yetcites [43] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“PD-L1 is induced by anti–CTLA-4–induced IFN-γ as a negative feedback mechanism to control irAEs.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Regardless of whether the effect is T cell intrinsic, the induction of PD-L1 in normal tissues is tissue-cell extrinsic.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 unexpected induction of PD-L1 was attributable to elevated IFN-γ production associated with LEM-induced expansion of IFN-γ–producing T cells, including Tc1 and Th1 cells.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“and the first in vivo genetic evidence that hypoxia is immunosuppressive for T and B cells of the adaptive immune system (37).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
What the sources say
- Not checked yetcites [37] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“This fundamental difference allows us to selectively inhibit PD-L1 expression in the TME using LEM.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“By preventing PD-L1 from interacting with PD-1, anti–PD-1/PD-L1 antibodies exacerbate irAEs caused by anti–CTLA-4 antibodies.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Subsequently, it was shown that direct elimination of TME hypoxia can improve cancer immunotherapy in mice (27, 38, 39).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 30
- Probably not a substantial claim. 15
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
“loss of Pdl1 (sh-Pdl1) in E0771 cells also inhibited tumor growth in C57BL/6, but not NSG, recipients (Figure 3B)”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 in tumor cells by targeting the HIF-1α/PD-L1 axis.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“TNF-α was unaffected by the therapies in CD4+ TILs, although we observed increased TNF-α+CD8+ TILs in groups receiving 9D9 (Supplemental Figure 5, E and F).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“The proportion of tumor-infiltrating NK cells expressing granzyme B and perforin were decreased and increased, respectively, in mice treated with 9D9 alone (Supplemental Figure 5, K and L).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“The inflammation was largely abrogated by LEM, as mice treated with ipilimumab plus LEM for the most part exhibited normal intestinal pathology (Figure 8F).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“The drug treatments had minimal impact on CD4+ TIL expression of CTLA-4 (Supplemental Figure 5B).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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
“Conditional knockout of Hif1a in T cells did not phenocopy the effects of LEM on PD-L1 induction in the liver, but PD-L1 induction was preserved regardless of the mouse genotype (Supplemental Figure 14).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“Annexin V staining revealed more apoptotic CD8+ and CD4+ TILs in tumors of 9D9-treated mice compared with vehicle, and adding LEM appeared to repress this effect in CD8+ TILs (Figure 6C).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“9D9 significantly increased and decreased the frequencies of effector and memory CD8+ T cells in the tumors, respectively (Supplemental Figure 6).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“Compared with vehicle, all treatments increased the frequencies of both IFN-γ+CD8+ (Tc1) and IFN-γ+CD4+ (Th1) subsets, although the highest frequencies of Tc1 were observed in mice receiving 9D9 plus LEM (Figure 5, E and F).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“The same trend was seen for CD4+ TILs, although the difference between the 9D9 and 9D9 plus LEM groups was not significant (Figure 6D).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“None of the therapies significantly impacted frequencies of tumor-infiltrating Treg or Th17 cells, except for a modest decrease in Tregs for groups receiving 9D9 (Supplemental Figure 5, I and J).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“Roughly one-fifth of CD4+ TILs were granzyme B+, which was not significantly affected by drug treatments (Figure 6G).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“we observed significant inhibition of tumor growth by LEM or 9D9 monotherapy compared with vehicle, while the greatest inhibition was achieved by 9D9 plus LEM or RMP1-14 (Figure 4, C and D).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > HIF-1α inhibition potentiates anti–CTLA-4 immunotherapy.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“E0771 mice treated with 9D9 had higher expression of exhaustion marker PD-1 on CD8+ TILs compared with vehicle, which was reversed by LEM (Figure 6A).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“LEM alone did not stimulate increased infiltration of T or NK cells in the tissues with PD-L1 expression (Figure 7, B–D, and Supplemental Figure 11), but led to a modest increase in IFN-γ detected in the serum (Supplemental Figure 12).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“These studies revealed that optimal efficacy required all 3 cell types, with CD8+ cells being the most critical, followed by NK and CD4+ cells (Figure 6I).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“the anti–IFN-γ neutralizing mAb XMG1.2, which abrogated PD-L1 induction by 9D9 plus LEM treatment and increased T cell infiltration in the kidneys and liver (Figure 7, B–D).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“the frequency of T cells as well as those of Tc1 and Th1 expanded in the spleen of mice that received 9D9 plus LEM treatment (Figure 7, E–G).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM induces PD-L1 expression to limit anti–CTLA-4–induced T cell infiltration in irAE target organs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“These results demonstrate that HIF-1α controls PD-L1 expression in E0771 cells and that echinomycin reduced PD-L1 by inhibiting the HIF-1α/PD-L1 axis.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > Targeting HIF-1α suppresses PD-L1 expression in the TME.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Thus, the immunotherapeutic effects of pharmacological HIF-1α inhibition in the context of anti–CTLA-4 are multiple-cell dependent, but primarily depend on CD8+ T cells.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“HIF-1α is generally inactivated in normal tissues but frequently stabilized in tumor cells regardless of oxygen tension (49, 50).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Here, we showed that targeting HIF-1α not only overcomes immune evasion in the TME, but also fortifies the immune tolerance checkpoint in normal tissues.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The current approach that overcomes tumor evasion of host immunity also disables the immune tolerance checkpoint, leading to significant irAEs, particularly when used in conjunction with anti–CTLA-4 antibodies.
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 results show that, in addition to tumor cells, in vivo HIF-1α inhibition can also suppress PD-L1 on tumor-infiltrating myeloid cells, and these effects persist in the context of anti–CTLA-4 therapy.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM inhibits PD-L1 on tumor cells and tumor-infiltrating myeloid cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The GI tract is the most frequent target of irAEs (31).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Results > LEM protected ipilimumab-induced irAEs in human CTLA4–knockin mice.
What the sources say
- Not checked yetcites [31] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1/PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment to achieve safer and more effective immunotherapy.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“On the other hand, studies by Johnson and colleagues found HIF-1α to be essential for myeloid cell–mediated inflammation (40).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
What the sources say
- Not checked yetcites [40] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“While HIF-1α has been shown to be involved in degradation of Foxp3 and induce the Th17 phenotype (26)”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
What the sources say
- Not checked yetcites [26] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. 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
“Sample sizes were chosen with adequate statistical power on the basis of the literature and past experience.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Methods > Statistics.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“Sitkovsky’s group originally demonstrated the first in vitro evidence that hypoxia is immunosuppressive for T cells (36)”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
What the sources say
- Not checked yetcites [36] source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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 experiments were replicated at least twice with similar results.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Methods > Statistics.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Thus, the data presented herein revealed a cancer cell–intrinsic inhibition of PD-L1 and normal tissue cell–extrinsic induction of PD-L1 by LEM.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“According to Doedens et al., HIFs enhance the effector responses of CD8+ T cells to persistent antigen (42).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
What the sources say
- Not checked yetcites [42] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“The induced PD-L1 is causatively associated with reduction in inflammation and intestinal leakage induced by anti–CTLA-4 antibodies, as it is abrogated by anti–PD-1 antibodies.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 procedures involving experimental animals were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Maryland School of Medicine.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Methods > Study approval.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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
“On day 6 after transplantation, mice were assigned to treatment groups such that comparable initial mean tumor volumes between experimental and control groups were achieved.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Methods > Tumor models.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“We have reported that echinomycin effectively eliminated leukemia stem cells (34).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
What the sources say
- Not checked yetcites [34] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Together, these 2 activities provide what we believe is the first example in cancer immunotherapy of an approach that abrogates the PD-1–PD-L1 checkpoint in the TME to eliminate immune evasion by cancer cells, while fortifying its immune tolerance checkpoint activity in normal tissues.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In T cells, HIF-1α is transiently stabilized in T cells following TCR activation (41), and plays an important role in regulating Treg and Th17 balance (26).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Targeting HIF-1α in immunotherapy is a relatively new concept, for which proof of principle has been amply demonstrated by others (12, 23, 27).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
What the sources say
Strength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“its function in inducing the Th1 phenotype has also been reported (51).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
What the sources say
- Not checked yetcites [51] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“In contrast to anti–PD-1, LEM not only further enhanced anti–CTLA-4–induced PD-L1 in normal tissue, but also allowed PD-L1 to signal through PD-1 to supercharge the immune tolerance checkpoint function.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“All animal experiments were conducted according to guidelines established by the NIH Guide for the Care and Use of Laboratory Animals (National Academies Press, 2011).”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Methods > Study approval.
What the sources say
- Not checked yetcites National Academies Press, 2011
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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
“Appropriate statistical tests were selected on the basis of whether the data with outlier deletion was normally distributed by using the D’Agostino & Pearson normality test.”
§ Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues > Methods > Statistics.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Clinical development of echinomycin for solid tumors has met with minimal success.
“However, clinical development of echinomycin for solid tumors has met with minimal success.”
The paper relies on this without support.
The current approach that overcomes tumor evasion of host immunity also disables the immune tolerance checkpoint, leading to significant irAEs, particularly when used in conjunction with anti–CTLA-4 antibodies.
“However, the current approach that overcomes tumor evasion of host immunity also disables the immune tolerance checkpoint, leading to significant irAEs, particularly when used in conjunction with anti–CTLA-4 antibodies.”
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
“Bailey, Liu, et al. in this issue demonstrate that targeting HIF-1α abrogated PD-L1–mediated immune evasion by suppressing PD-L1 expression on malignant and myeloid regulatory cells, causing tumor rejection.”
From Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy (2022) · cites this paper as [24]
In the citing paper
“Bailey, Liu, et al. confirmed these results (24).”
From Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy (2022) · cites this paper as [24]
In the citing paper
“Importantly, HIF-1α inhibition potentiated immunotherapeutic effects of anti–CTLA-4 therapy in experimental models.”
From Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy (2022) · cites this paper as [24]
In the citing paper
“HIF-1α inhibition in vivo downregulated PD-1 expression, upregulated cytolytic effector molecules granzyme B and perforin, and decreased apoptosis in TILs in the tumor microenvironment.”
From Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy (2022) · cites this paper as [24]
In the citing paper
“Promotion of immune tolerance by differential regulation of PD-L1 in normal and cancer tissues is an important approach for safer and more successful immunotherapy (24).”
From Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy (2022) · cites this paper as [24]
In the citing paper
“The authors also reported an interesting observation; although HIF-1α inhibition blocked PD-L1 expression at the tumor site, it induced PD-L1 in normal tissues.”
From Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy (2022) · cites this paper as [24]
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
Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
Wanchoo, R., Karam, S., Uppal, N. N., Barta, V. S., Deray, G., Devoe, C., Launay‐Vacher, V., Jhaveri, K. D., & on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors (2017) · American Journal of Nephrology · doi:10.1159/000455014 · Cited by 15,320
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Cowey, C. L., Lao, C. D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504030 · Cited by 8,157
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717 · cited 1×
“Discussion HIF-1α inhibition is an area of active investigation in cancer therapy (32, 33).”
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Wolchok, J. D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J.-J., Cowey, C. L., Lao, C. D., Wagstaff, J., Schadendorf, D., Ferrucci, P. F., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1709684 · Cited by 5,357
Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion
Dong, H., Strome, S. E., Salomao, D. R., Tamura, H., Hirano, F., Flies, D. B., Roche, P. C., Lu, J., Zhu, G., Tamada, K., et al. (2002) · Nature Medicine · doi:10.1038/nm730 · Cited by 5,025
Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients
Locatelli, F., Fishbane, S. N., Block, G. A., & Macdougall, I. C. (2017) · American Journal of Nephrology · doi:10.1159/000455166 · Cited by 4,836
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma
Motzer, R. J., Tannir, N. M., McDermott, D. F., Arén Frontera, O., Melichar, B., Choueiri, T. K., Plimack, E. R., Barthélémy, P., Porta, C., George, S., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1712126 · Cited by 4,656
Restoring function in exhausted CD8 T cells during chronic viral infection
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Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.-J., Rutkowski, P., Lao, C. D., Cowey, C. L., Schadendorf, D., Wagstaff, J., Dummer, R., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1910836 · Cited by 3,723 · cited 3×
“In terms of therapeutic efficacy, anti–CTLA-4 plus anti–PD-1 combination therapy is considered the most effective immunotherapy strategy (5).”
Flagged first, then by citations
2 of the 58 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Regulatory mechanisms of PD-1/PD-L1 in cancers
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Metabolic reprogramming in cancer: Mechanisms and therapeutics
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Self-citation
Metadata
- Authors
- Bailey, C. M., Liu, Y., Liu, M., Du, X., Devenport, M., Zheng, P., Liu, Y., & Wang, Y.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Liu, Yang
- Wang, Yin
- Venue
- Journal of Clinical Investigation
- Published
- 2022-05-02
- Volume
- 132
- Issue
- 9
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC9057613
- OpenAlex
- W4214881895
- Semantic Scholar
- 61d954ba1fe3c4cba513f816261e83f90b00fc87
- Cited by
- 151
- References
- 58
- Citations by year
- 2026: 34 · 2025: 45 · 2024: 38 · 2023: 24 · 2022: 10
- FWCI
- 12.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (CA171972, CA183030, CA219150, CA227671)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- HIF-1α, PD-L1, immune evasion, tumor microenvironment, immune-related adverse events, CTLA-4, PD-1/PD-L1 immune checkpoint, echinomycin, interferon-gamma, tumor-infiltrating myeloid cells, tumor-infiltrating lymphocytes, cancer immunotherapy
- MeSH terms
- Animals, Echinomycin, Immune Tolerance, Neoplasms, Lymphocytes, Tumor-Infiltrating, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Immune Evasion, Tumor Microenvironment, B7-H1 Antigen
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 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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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