TET2 Promotes Tumor Antigen Presentation and T Cell-Directed Tumor Cell Cytotoxicity Which is Enhanced by Vitamin C Treatment

Immune evasion by tumors is promoted by low T cell infiltration, an immunosuppressive tumor microenvironment, poor T cell activity directed against the tumor, and reduced tumor antigen presentation. We showed previously that tumor expression of the DNA dioxygenase TET2 enhances recruitment of T cells through activating the expression of CXCL9, 10 and 11. Vitamin C treatment was shown to increase these effects in a TET2 dependent manner. Using scSeq analysis, we show that an additional function for TET2 in tumors is to enhance the expression of genes involved in antigen presentation, including those encoding H-2 MHC proteins, B2M, TAP1, TAPBP, and components of immunoproteasome. Using the B16-OVA melanoma model, we show that antigen expression in tumors is blocked if TET2 expression is eliminated and that vitamin C further promotes tumor antigen presentation in a TET2-dependent manner. Consistently, T cell killing assays demonstrate that effective killing of tumor by antigen-specific T cells requires TET2 expression in the tumor cells. Analysis of patient tumor samples indicates that TET2 activity, as measured through 5hmC levels, correlates directly with expression of antigen-presentation gene expression and with patient outcomes.