Ptpn2 deletion increased the ratio of TIM3+ terminally exhausted to SLAMF6+ progenitor CD8+ T cells.
Major Finding: Ptpn2 deletion increased the ratio of TIM3+ terminally exhausted to SLAMF6+ progenitor CD8+ T cells.
Concept: Ptpn2 deletion in hematopoietic cells improved ICB efficacy and the antitumor response in mice.
Impact: PTPN2 deletion in chimeric antigen receptor T-cell therapies or PTPN2 inhibitors may be of interest.
Exhausted CD8+ T cells resulting from chronic viral infection or cancer can be divided into two groups: a progenitor population, defined as PD-1intCXCR5+ or SLAMF6+, and a terminally exhausted population, defined as PD-1hi 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.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.