Hypoxia promotes tumor immune evasion by suppressing MHC-I expression and antigen presentation.

Hypoxia is a common feature of solid tumors that has previously been linked to resistance to radiotherapy and chemotherapy, and more recently to immunotherapy. In particular, hypoxic tumors exclude T cells and inhibit their activity, suggesting that tumor cells acquire a mechanism to evade T-cell recognition and killing. Our analysis of hypoxic tumors indicates that hypoxia downregulates the expression of MHC class I and its bound peptides (i.e., the immunopeptidome). Hypoxia decreases MHC-I expression in an oxygen-dependent manner, via activation of autophagy through the PERK arm of the unfolded protein response. Using an immunopeptidomics-based LC-MS approach, we find a significant reduction of presented antigens under hypoxia. Inhibition of autophagy under hypoxia enhances antigen presentation. In experimental tumors, reducing mitochondrial metabolism through a respiratory complex-I inhibitor increases tumor oxygenation, as well as MHC-I levels and the immunopeptidome. These data explain the molecular basis of tumor immune evasion in hypoxic conditions, and have implications for future therapeutic interventions targeting hypoxia-induced alterations in antigen presentation. Synopsis: Hypoxia contributes to cancer resistance to both standard therapies and immunotherapy. This work demonstrates that tumor hypoxia promotes immune evasion by autophagy-mediated downregulation of MHC class I expression leading to reduced antigen presentation. Hypoxia decreases MHC-I expression and the abundance of the immunopeptidome, leading to immune evasion. Activation of autophagy through the PERK arm of the unfolded protein response promotes lysosomal MHC-I degradation. Inhibiting autophagy under hypoxic conditions rescues MHC-I expression and restores immunopeptidome abundance unveiling new antigens. Preventing MHC-I degradation under hypoxia enhances recognition of hypoxic cells by CD8+ T cells. Activation of autophagy and lysosomal MHC-I degradation under low oxygen downregulates the immunopeptidome, explaining therapy resistance of hypoxic tumors. [ABSTRACT FROM AUTHOR]