Hypoxia-associated mRNA epitranscriptomic modifications block the translation of antigen processing machinery

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B146
Abstract ID: 5195

Presenting Author:
Alexis R Ramos , Graduate Research Assistant at Univ. of Iowa Carver Col. of Med.

Abstract:

Antigen processing is critical for adaptive immunity but is often subverted in cancer. While hypoxia is pervasive in solid tumors, its effects on antigen processing are unknown. Here, we cultured a variety of cancer cells in normoxic or hypoxic conditions and treated with interferon (IFN)-γ to induce antigen processing machinery (APM). IFN-γ induced APM under normoxia, including the immunoproteasome, endoplasmic reticulum (ER) peptide transporters, and ER-associated chaperones / peptide-loading complex. In contrast, IFN-γ failed to induce APM under hypoxia. Surprisingly, induction of corresponding APM mRNAs were intact under hypoxia, indicating APM blockade occurs post-transcriptionally. Genetic deletion of hypoxia-inducible factors (HIF) failed to restore APM induction, indicating APM blockade is independent of HIF signaling. 5-Azacytidine (5aza), a cystine methyltransferase (MTase) inhibitor favoring RNA integration, reversed hypoxic APM blockade, while decitabine (DAC); a cystine MTase inhibitor only integrating DNA, did not, suggesting APM blockade involves RNA methylation. Supporting this, highly elevated 5-methylcytosine (5mC) mRNA levels were observed under hypoxia that were abrogated by 5aza but not DAC. Current efforts include mapping hypoxic 5mC mRNA sites and investigating MTase(s) behind hypoxic APM blockade. These studies reveal a novel mode of tumor immune evasion mediated by hypoxia and establish a novel role for epitranscriptomics in governing immunogenicity.