Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues
Christopher M. Bailey, … , Yang Liu, Yin Wang
Christopher M. Bailey, … , Yang Liu, Yin Wang
Published March 3, 2022
Citation Information: J Clin Invest. 2022;132(9):e150846. https://doi.org/10.1172/JCI150846.
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Research Article Therapeutics

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

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.

Authors

Christopher M. Bailey, Yan Liu, Mingyue Liu, Xuexiang Du, Martin Devenport, Pan Zheng, Yang Liu, Yin Wang

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Figure 2

Therapeutic effects of echinomycin on tumor growth in immunodeficient and immunocompetent mice.

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Therapeutic effects of echinomycin on tumor growth in immunodeficient an...
Three murine tumor lines were tested: 4T1, E0771, and MC38. For each, immunodeficient (NSG) and immunocompetent (BALB/c or C57BL/6) mice were inoculated (day 0), and treatment was initiated with control liposomes (vehicle) or echinomycin liposomes (LEM) on day 6 (blue arrows indicate a single treatment). Tumor growth kinetics were compared to deduce the role of adaptive immunity in the therapeutic effects of echinomycin. (A) Diagram of experimental design. (B) NSG and BALB/c mice received 4T1 cells (1 × 106/mouse) and were treated with vehicle or 0.15 mg/kg LEM (n = 10/group). Mean tumor volumes ± SEM are shown and were analyzed by 2-way ANOVA. The data are representative of 2 independent experiments. (C) NSG and C57BL/6 mice received E0771 cells (0.7 × 106/mouse) and were treated with vehicle or 0.25 mg/kg LEM (n = 5/group). Mean tumor volumes ± SEM are shown and were analyzed by 2-way ANOVA. The data are representative of 2 independent experiments. (D) NSG and C57BL/6 mice received MC38 cells (1 × 106/mouse) and were treated with vehicle or 0.15 mg/kg LEM (n = 5/group). Mean tumor volumes ± SEM are shown, which were analyzed by 2-way ANOVA. The data are representative of 2 independent experiments. *P < 0.05; **P < 0.01; ****P < 0.0001.