CoChat
Sign Up
Cited by 152Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesCancer, Hypoxia, and Metabolism

Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues

Open access
Bailey, Christopher M., Liu, Yan, Liu, Mingyue, Du, Xuexiang, Devenport, Martin, Zheng, Pan, Liu, Yang, Wang, Yin·2022·Journal of Clinical Investigation
DOI 10.1172/jci150846PMC PMC9057613
Open this paper in CoChat — free accountOpen PDF

Abstract

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.

AI snapshot

Written from the paper’s full text.

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1172/jci150846

Cites

56 of 56 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 22 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In the E0771 model, therapeutic effects of LEM are more pronounced in immune-competent mice.

    “In a second breast cancer model, E0771, the therapeutic effects of LEM were also more pronounced in immune-competent mice (Figure 2C).”
    Quote in the paperSubstantial claim
  • Findingown data

    LEM significantly inhibits 4T1 growth in both immunocompetent BALB/c and immunodeficient NSG recipients compared with respective vehicle controls.

    “LEM significantly inhibited 4T1 growth in both immunocompetent (BALB/c) and immunodeficient (NSG) recipients compared with each strain’s respective vehicle control (Figure 2B).”
    Quote in the paperSubstantial claim
  • Findingown data

    LEM does not further suppress sh-Pdl1 E0771 tumor growth in C57BL/6 or NSG recipients.

    “LEM did not further suppress sh-Pdl1 E0771 tumor growth in C57BL/6 (Figure 3C) or NSG (Figure 3D) recipients.”
    Quote in the paperSubstantial claim
  • Findingown data

    Liposome-encapsulated echinomycin (LEM) markedly reduces intratumoral PD-L1 expression in engrafted tumor cell lines.

    “there was a marked reduction in PD-L1 expression in the tumors of LEM-treated mice.”
    Quote in the paperSubstantial claim
  • Findingown data

    LEM more effectively inhibits sh-Scr E0771 tumor growth in C57BL/6 compared with NSG recipients.

    “LEM more effectively inhibited sh-Scr E0771 tumor growth in C57BL/6 (Figure 3C) compared with NSG (Figure 3D) recipients”
    Quote in the paperSubstantial claim
  • May combine two claims. 30
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingown data

    Loss of Pdl1 (sh-Pdl1) in E0771 cells inhibits tumor growth in C57BL/6 but not NSG recipients.

    “loss of Pdl1 (sh-Pdl1) in E0771 cells also inhibited tumor growth in C57BL/6, but not NSG, recipients (Figure 3B)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TNF-α was unaffected by the therapies in CD4+ TILs, although increased TNF-α+CD8+ TILs were observed in groups receiving 9D9.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The proportion of tumor-infiltrating NK cells expressing granzyme B and perforin were decreased and increased, respectively, in mice treated with 9D9 alone.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LEM largely abrogated ipilimumab-induced intestinal inflammation, with most mice treated with ipilimumab plus LEM exhibiting normal intestinal pathology.

    “The inflammation was largely abrogated by LEM, as mice treated with ipilimumab plus LEM for the most part exhibited normal intestinal pathology (Figure 8F).”
    Quote in the paperSubstantial claim

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

    Findingown data

    The drug treatments had minimal impact on CD4+ TIL expression of CTLA-4.

    “The drug treatments had minimal impact on CD4+ TIL expression of CTLA-4 (Supplemental Figure 5B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    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.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    More apoptotic CD8+ and CD4+ TILs were found in tumors of 9D9-treated mice compared with vehicle, and adding LEM appeared to repress this effect in CD8+ TILs.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    9D9 significantly increased and decreased the frequencies of effector and memory CD8+ T cells in the tumors, respectively.

    “9D9 significantly increased and decreased the frequencies of effector and memory CD8+ T cells in the tumors, respectively (Supplemental Figure 6).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Compared with vehicle, all treatments increased the frequencies of IFN-γ+CD8+ (Tc1) and IFN-γ+CD4+ (Th1) subsets, although the highest frequencies of Tc1 were observed in mice receiving 9D9 plus LEM.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The same trend for apoptosis was seen for CD4+ TILs, although the difference between the 9D9 and 9D9 plus LEM groups was not significant.

    “The same trend was seen for CD4+ TILs, although the difference between the 9D9 and 9D9 plus LEM groups was not significant (Figure 6D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    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.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Roughly one-fifth of CD4+ TILs were granzyme B+, which was not significantly affected by drug treatments.

    “Roughly one-fifth of CD4+ TILs were granzyme B+, which was not significantly affected by drug treatments (Figure 6G).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LEM or 9D9 monotherapy significantly inhibits tumor growth compared with vehicle, while the greatest inhibition is achieved by 9D9 plus LEM or RMP1-14.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    E0771 mice treated with 9D9 had higher expression of exhaustion marker PD-1 on CD8+ TILs compared with vehicle, which was reversed by LEM.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LEM alone did not stimulate increased infiltration of T or NK cells in the tissues with PD-L1 expression, but led to a modest increase in IFN-γ detected in the serum.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Optimal efficacy of 9D9 plus LEM in E0771 mice required CD4+, CD8+, and NK cells, with CD8+ cells being the most critical, followed by NK and CD4+ cells.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The anti-IFN-γ neutralizing mAb XMG1.2 abrogated PD-L1 induction by 9D9 plus LEM treatment and increased T cell infiltration in the kidneys and liver.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    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.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    HIF-1α controls PD-L1 expression in E0771 cells and echinomycin reduces PD-L1 by inhibiting the HIF-1α/PD-L1 axis.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    HIF-1α is generally inactivated in normal tissues but frequently stabilized in tumor cells regardless of oxygen tension.

    “HIF-1α is generally inactivated in normal tissues but frequently stabilized in tumor cells regardless of oxygen tension (49, 50).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [49] source

      Not checked in the free run.

    • cites [50] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Targeting HIF-1α not only overcomes immune evasion in the TME, but also fortifies the immune tolerance checkpoint in normal tissues.

    “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.”
    Quote in the paperSubstantial claim
    • 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.

  • May combine two claims.

    Interpretationown data

    In vivo HIF-1α inhibition can suppress PD-L1 on tumor-infiltrating myeloid cells, and these effects persist in the context of anti-CTLA-4 therapy.

    “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.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The GI tract is the most frequent target of irAEs.

    “The GI tract is the most frequent target of irAEs (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    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.

    “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.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    HIF-1α is essential for myeloid cell-mediated inflammation.

    “On the other hand, studies by Johnson and colleagues found HIF-1α to be essential for myeloid cell–mediated inflammation (40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] source

      Not checked in the free run.

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

    Premisecitation

    HIF-1α has been shown to be involved in degradation of Foxp3 and induce the Th17 phenotype.

    “While HIF-1α has been shown to be involved in degradation of Foxp3 and induce the Th17 phenotype (26)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] source

      Not checked in the free run.

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

    Study design and conductnone given

    Sample sizes were chosen with adequate statistical power on the basis of the literature and past experience.

    “Sample sizes were chosen with adequate statistical power on the basis of the literature and past experience.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Hypoxia is immunosuppressive for T cells (in vitro evidence).

    “Sitkovsky’s group originally demonstrated the first in vitro evidence that hypoxia is immunosuppressive for T cells (36)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] source

      Not checked in the free run.

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

    Study design and conductnone given

    All experiments were replicated at least twice with similar results.

    “All experiments were replicated at least twice with similar results.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    LEM causes cancer cell-intrinsic inhibition of PD-L1 and normal tissue cell-extrinsic induction of PD-L1.

    “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.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    HIFs enhance the effector responses of CD8+ T cells to persistent antigen.

    “According to Doedens et al., HIFs enhance the effector responses of CD8+ T cells to persistent antigen (42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    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.

    “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.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All procedures involving experimental animals were approved by IACUC of University of Maryland School of Medicine.

    “All procedures involving experimental animals were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Maryland School of Medicine.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    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.

    “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.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Echinomycin effectively eliminated leukemia stem cells.

    “We have reported that echinomycin effectively eliminated leukemia stem cells (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    This approach provides 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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In T cells, HIF-1α is transiently stabilized following TCR activation and plays an important role in regulating Treg and Th17 balance.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] source

      Not checked in the free run.

    • cites [26] source

      Not checked in the free run.

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

    Premisecitation

    Targeting HIF-1α in immunotherapy is a relatively new concept, for which proof of principle has been amply demonstrated by others.

    “Targeting HIF-1α in immunotherapy is a relatively new concept, for which proof of principle has been amply demonstrated by others (12, 23, 27).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12] source

      Not checked in the free run.

    • cites [23] source

      Not checked in the free run.

    • cites [27] Hatfield, 2015, Immunological mechanisms of the antitumor effects of supplemental oxygenation, Sci Transl Med source

      Not checked in the free run.

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

    Premisecitation

    HIF-1α function in inducing the Th1 phenotype has been reported.

    “its function in inducing the Th1 phenotype has also been reported (51).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    LEM further enhanced anti-CTLA-4-induced PD-L1 in normal tissue and allowed PD-L1 to signal through PD-1 to supercharge the immune tolerance checkpoint function.

    “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.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    All animal experiments were conducted according to NIH Guide for the Care and Use of Laboratory Animals.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites National Academies Press, 2011

      Not checked in the free run.

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

    Study design and conductown data

    Appropriate statistical tests were selected based on normality testing using D'Agostino & Pearson normality test.

    “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.”
    Quote in the paperNot a substantial claim
43 of 43

  • 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.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Bailey, Liu, et al. demonstrated that targeting HIF-1α abrogated PD-L1-mediated immune evasion by suppressing PD-L1 expression on malignant and myeloid regulatory cells, causing tumor rejection.

    “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]

  • Bailey, Liu, et al. confirmed these results.

    “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]

  • HIF-1α inhibition potentiated immunotherapeutic effects of anti-CTLA-4 therapy in experimental models.

    “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]

  • 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.

    “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]

  • 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.

    “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]

Cites

Flagged first, then by citations

2 of the 58 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

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
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2022-05-02
Volume
132
Issue
9
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci150846
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
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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review