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

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

doi:10.1172/jci150846

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.

Highlights

Current immunotherapeutic strategies, articulated as immune checkpoint blockade, aim to release physiological immune tolerance checkpoints for the benefit of immunotherapeutic effect
Since tumor cells express HIF-1α under normoxia, we tested whether the HIF-1α/programmed death ligand 1 (PD-L1) axis is active in tumor cells stably expressing HIF-1α under normoxic conditions
We first examined levels of HIF-1α and PD-L1 in the murine breast cancer cell lines 4T1 and E0771 cultured under normoxia. Both cell lines expressed HIF-1α and PD-L1 protein (Figure 1, A and B; see complete unedited blots in the supplemental material), and a reduction in PD-L1 protein was observed in cells treated with the HIF-1α inhibitor echinomycin (Figure 1B)

Summary

Introduction

Current immunotherapeutic strategies, articulated as immune checkpoint blockade, aim to release physiological immune tolerance checkpoints for the benefit of immunotherapeutic effect. Immune-related adverse events (irAEs) are considered the necessary price for immunotherapy. The relative risk/benefit ratio depends on the significance of the immune checkpoint in immune tolerance versus tumor evasion of host immunity. The PD-1–PD-L1 interaction is less critical than CTLA-4 for immune tolerance, as CTLA-4 inactivation leads to more severe autoimmune diseases than inactivation of PD-1 [1–4]. In terms of therapeutic efficacy, anti–CTLA-4 plus anti–PD-1 combination therapy is considered the most effective immunotherapy strategy [5]. The combination substantially increases rates of severe irAEs [5] to 50%–90%, depending on therapeutic setting [6–9]. A major challenge for cancer immunotherapy is to eliminate irAEs without compromising synergistic cancer immunotherapeutic effects of dual immune checkpoint blockade

Methods

Results

Conclusion