| Summary: | 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
MHC I expression and its bound peptides (the immunopeptidome). Hypoxia decreases MHC I
expression in an oxygen-dependent manner, mediated by the activation of autophagy through the
PERK arm of the unfolded protein response. Using an immunopeptidomics-based LC-MS approach,
we found a significant reduction in presented antigens under hypoxia. Inhibition of autophagy under
hypoxia enhanced antigen presentation. In experimental tumors, reducing mitochondrial metabolism
through a complex I inhibitor increases tumor oxygenation and both MHC I levels as well as the
immunopeptidome. These data provide the molecular mechanism governing tumor immune evasion in
hypoxic conditions, offering novel insights for therapeutic interventions targeting hypoxia-induced
alterations in antigen presentation.
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