PTPN2 regulates the generation of exhausted CD8.sup.+ T cell subpopulations and restrains tumor immunity

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