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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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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.
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Figures
![Figure 6 Echinomycin improves TIL function in anti–CTLA-4–treated mice and CD8+ TILs are critical for combination efficacy. (A–H) C57BL/6 mice received E0771 cells (0.5 × 106/mouse) on day 0 followed by treatment with vehicle, echinomycin (LEM, 0.25 mg/kg/dose), 9D9 (0.2 mg/mouse/dose), or 9D9 plus LEM on days 6, 8, and 10. On day 14, tumors were analyzed by flow cytometry. Each graph shows the frequencies of CD8+ or CD4+ subsets among TILs (gated on live CD45+CD3+CD8+CD4– singlets or live CD45+CD3+CD8–CD4+ singlets). Data are representative of 2 experiments and presented as the mean ± SEM of each group (n = 5/group), and were analyzed by unpaired, 2-tailed Student’s t test. (A and B) Frequencies of TILs expressing PD-1. (C and D) Frequencies of annexin V+ TILs. (E and F) Frequencies of CD8+ TILs expressing granzyme B or perforin. (G and H) Granzyme B and perforin expression in CD8+ TILs. (I and J) Granzyme B and perforin expression in CD4+ TILs. (J) Effect of depletion of CD4+, CD8+, or NK cells on tumor growth inhibition by 9D9 plus LEM in the syngeneic E0771 model. C57BL/6 mice received E0771 cells (0.5 × 106/mouse) on day 0. On day 5, the mice were randomized to receive depleting antibodies (500 μg of anti-CD4 [GK1.5], anti-CD8 [YTS169.4], anti-NK1.1 [PK136], or isotype control). All groups received 9D9 (200 μg) on day 6, and LEM (250 μg/kg) on days 6, 8, and 10. Mice received supplemental dose of depleting antibodies (200 μg) on days 8 and 10. The mean ± SEM tumor volumes are plotted on the y axes for each group (n = 5/group) and were analyzed by 2-way ANOVA. Representative data shown for 1 of 2 experiments. *P < 0.05; ***P < 0.001; ****P < 0.0001.](/paper-figures/0802536701ed42cfb1323d248e6b9d45/targeting-hif-1-abrogates-pd-l1mediated-immune-evasion-in-tumor-microenvironment-figure-6.jpg)
Verification
Claims the paper makes
75 Own result · 30 Own interpretation · 15 Not checked yet · 5 Own method · 1 Partly supported · 1 No basis given · accuracy not yet measured
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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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“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.
plaindirect- Asserted: passes — The authors put it forward as true.
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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
- Partly supportedcites [12] sourceExperimental — accuracy not yet measured
The Results and Discussion (page unavailable in our copy) show that HIF-1α drives PD-L1 expression under hypoxia and that PD-L1 blockade reduces MDSC-mediated T-cell suppression. The paper proposes combining HIF-1α inhibitors with PD-L1 blockade, but does not demonstrate that HIF-1α-targeted immunotherapy works or establish that its proof of principle has been amply demonstrated by others. (LLM, conf=0.85)
- Not checked yetcites [23] source
- Partly supportedcites [27] Hatfield, 2015, Immunological mechanisms of the antitumor effects of supplemental oxygenation, Sci Transl Med sourceExperimental — accuracy not yet measured
The Study design section describes mouse experiments as proof of principle for using respiratory hyperoxia to counter hypoxia-driven immunosuppression and improve tumor rejection. The Discussion links HIF-1α to immunosuppressive mechanisms, but the study tests supplemental oxygen, not HIF-1α targeting, and does not establish that such targeting is a relatively new concept. (LLM, conf=0.77)
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- Partly supported
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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.
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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.
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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.
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“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.
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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.
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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.
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“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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The 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
Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B., Allison, J. P., Sharpe, A. H., Freeman, G. J., & Ahmed, R. (2005) · Nature · doi:10.1038/nature04444 · Cited by 4,057
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).”
Cited by
Sorted by citations
Regulatory mechanisms of PD-1/PD-L1 in cancers
Lin, X., Kang, K., Chen, P., Zeng, Z., Li, G., Xiong, W., Yi, M., & Xiang, B. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02023-w · Cited by 909
“Hypoxic conditions induce the activation of hypoxia-inducible factor-1α (HIF-1α) and the accumulation of lactic acid, with both HIF-1α and HIF-2α being able to directly bind to the hypoxia response element in the PD-L1 promoter region, participating in the transcriptional regulation of PD-L1 [224].”
BackgroundMetabolic reprogramming in cancer: Mechanisms and therapeutics
Nong, S., Han, X., Yu, X., Qian, Y., Wei, Y., Zhang, T., Tian, K., Shen, K., Yang, J., & Ma, X. (2023) · MedComm · doi:10.1002/mco2.218 · Cited by 313
PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy
Li, Q., Han, J., Yang, Y., & Chen, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1070961 · Cited by 255
Regulatory T cells in immune checkpoint blockade antitumor therapy
Zhang, A., Fan, T., Liu, Y., Yu, G., Li, C., & Jiang, Z. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02156-y · Cited by 174
“However, through an IFNγ-dependent mechanism, it elevated PD-L1 expression in normal tissues, abolished the PD-1/PD-L1 checkpoint in the TME, diminished Treg-mediated immunosuppression and enhanced immune tolerance checkpoint activity in normal tissues [188].”
BackgroundSelf-citationRibonucleotide reductase M2 (RRM2): Regulation, function and targeting strategy in human cancer
Zuo, Z., Zhou, Z., Chang, Y., Liu, Y., Shen, Y., Li, Q., & Zhang, L. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2022.11.022 · Cited by 132
“Moreover, targeting HIF-1a can also suppress PD-L1 expression in tumor cells.(157) In breast cancer, Shah et al showed that RRM2 overexpression specifically up-regulates HIF-1a.”
BackgroundSelf-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).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
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