PTPN2 regulates the generation of exhausted CD8(+) T cell subpopulations and restrains tumor immunity

CD8(+) T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6(+) progenitor exhausted and Tim-3(+) terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a novel regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8(+) T cells increased the generation, proliferative capacity, and cytotoxicity of Tim-3(+) cells without altering Slamf6(+) numbers during LCMV Clone 13 infection. Likewise, Ptpn2-deletion in CD8(+) T cells enhanced Tim-3(+) anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved PD-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3(+) CD8(+) T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.