Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy

Abstract

Tumor-associated hypoxia plays an important role in carcinogenesis and metastasis. The expression, activation, and stabilization of hypoxia-inducible transcription factors (HIFs) support malignant cell survival, proliferation, plasticity, and motility. Hypoxia also upregulates the expression of programmed cell death ligand 1 (PD-L1) in malignant and immune regulatory cells. Therefore, the combination of HIF inhibitors and checkpoint inhibitors (CPIs) is promising for boosting antitumor immunity and diminishing malignant cell plasticity and therapy resistance. In this issue of the JCI, Salman et al. report the development of a specific agent that inhibited HIF-1/2-mediated gene expression in tumor cells and suppressed tumor growth. 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. These findings suggest that targeting the HIF/PD-L1 axis with specific HIF inhibitors should improve the safety and efficacy of CPIs for cancer therapy.

Figure 1. Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy.

A majority of solid tumors develop hypoxia because of chaotic vascularization leading to deprivation of optimal oxygen supply and increased cellular proliferation and metabolic rate. Hypoxia causes the activation and stabilization of key transcription factors, the hypoxia-inducible transcription factors (HIFs). HIF-1α and HIF-2α control the expression of many tumorigenesis genes. HIFs promote tumor progression by stimulating angiogenesis, immunosuppression, EMT, and metabolic reprogramming, and by supporting malignant cell survival, motility, proliferation, plasticity, and enhancing treatment resistance and escape from a nutrient-deprived milieu. Hypoxia also upregulates the expression of PD-L1 in malignant cells and MDSCs via HIF-1α and HIF-2α. PD-L1, via binding to its receptor (PD-1), acts as a protumorigenic factor that induces immune tolerance within the tumor microenvironment and inhibits antitumor immune responses by suppressing activity of tumor-specific TILs. HIF inhibition synergizes with CPIs to block tumor development and progression. Further studies should determine how other factors in the tumor milieu, such as cytokines, chemokines, growth factors, hormones, and therapeutic agents, may interfere with the antitumor potential of a combination of HIF inhibitors and CPI therapy.