Combined inhibition of homologous PTPN1 and PTPN2 is synergistic in enhancing CD8 T cell effector functions.
Increased understanding of the modulatory pathways controlling CD8 T cell responses has led to the formulation of successful checkpoint inhibitor-based immunotherapies against cancer. However, their effectiveness is limited to a few tumor types, motivating the search for novel combinatorial strategies. PTPN1 and PTPN2 are two homologous protein tyrosine phosphatases recently proposed as potent intracellular checkpoints. Furthermore, their catalytic domain is a propitious target for small-molecule pharmacological intervention. Herein we investigated the potential effects of conditional genetic deletion of either or both phosphatases in mouse CD8 T cells, one of the main effectors in cancer immunotherapy. Our results demonstrated that hemizygous deletion of PTPN1 in a PTPN2 deficient background heightens the enhanced effector phenotype already observed in PTPN2 defective CD8 T cells. This functional gain is mediated by an autocrine IL-10 positive feedback loop. Pharmacological inhibition with a PTPN1/2 small-molecule inhibitor yielded similar results, highlighting the importance of simultaneously inhibiting both phosphatases. Our study uncovers a novel mechanism by which the downregulation of PTPN1 and PTPN2 act as a powerful tool for potentiating CD8 cytotoxic responses.