PTPN2 Mediates Production of Exhausted T Cells and Antitumor Immunity

Exhausted CD8⁺ T cells resulting from chronic viral infection or cancer can be divided into two groups: a progenitor population, defined as PD-1^intCXCR5⁺ or SLAMF6⁺, and a terminally exhausted population, defined as PD-1^hi or TIM3⁺. In a mouse model of lymphocytic choriomeningitis virus (LCMV) clone 13 infection, LaFleur and colleagues found that deletion of the gene encoding the phosphatase PTPN2 provided a temporary advantage to CD8⁺ T cells early in infection, promoting their proliferation. Ptpn2 deletion increased the ratio of TIM3⁺ terminally exhausted T cells to SLAMF6⁺ T cells by increasing the number of TIM3⁺ cells while the number of SLAMF6⁺ cells remained constant. Further experiments revealed that Ptpn2 deletion increased conversion of SLAMF6⁺ cells into TIM3⁺ cells while also increasing the proliferation of both cell types. After 30 days of LCMV infection, at which point canonical features of T-cell exhaustion were present, transcription of effector-related and cytotoxicity-associated genes was increased in Ptpn2-deleted progenitor and terminally exhausted cells. In vivo, IFN1 signaling was essential for the increased differentiation of TIM3⁺ cells following Ptpn2 deletion. In agreement with the results in the LCMV model, in a mouse model of colorectal cancer, Ptpn2-deleted CD8⁺ T cells exhibited increased differentiation, outcompeted control cells, showed elevated granzyme B expression, and improved tumor control. Deletion of Ptpn2 in all hematopoietic cells increased the CD8⁺ T-cell responses to tumors in this model and improved response to immune checkpoint blockade (ICB) with anti–PD-1. In summary, this study uncovered a previously unknown role for PTPN2 in mediating the ratio of TIM3⁺ to SLAMF6⁺ cells; further, it supports the investigation of PTPN2 inhibitors combined with ICB or deletion of PTPN2 in chimeric antigen receptor T-cell therapies.

LaFleur MW, Nguyen TH, Coxe MA, Miller BC, Yates KB, Gillis JE, et al. PTPN2 regulates the generation of exhausted CD8⁺ T cell subpopulations and restrains tumor immunity. Nat Immunol 2019;20:1335–47.

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