Loss of OGT enhances type I interferon-dependent antitumor immunity

Abstract

Abstract The O-GlcNAc transferase (OGT) is an essential enzyme that mediates protein O-GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O-GlcNAcylation level in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent hosts via repressing cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (Ogt−/−) caused a markedly reduction in tumor growth in both syngeneic tumor models and genetic colorectal cancer (CRC) model induced by mutation of the Apcgene (Apcmin). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgasfrom Ogt−/−MC38 CRC cells restored tumor growth, which correlated with impaired CD8+ T cell antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production. In sum, our results identify OGT-mediated genomic stability as an important tumor cell-intrinsic mechanism to repress antitumor immunity. Supported by the National Institutes of Health R01GM120496 (H.W.)