Abstract 2166: PTPN1/2 dual inhibition sensitizes solid tumors to checkpoint blockade immunotherapy by enhancing T cell cytotoxicity and by decreasing cancer cell immune evasion

Abstract Immunotherapy has revolutionized the way we treat patients suffering from cancer. However, many patients are still refractory to immunotherapy, which highlights the importance of identifying new genetic targets that can achieve therapeutic outcomes. Recent work has revealed that protein tyrosine phosphatase non-receptor 2 (PTPN2) can act as such a target by enhancing T-cell and interferon responses against cancer. Development of PTPN2 inhibitors paves the way for a new therapeutic modality to fight solid malignancies. However, current inhibitors also inhibit PTPN1, a closely related phosphatase with largely different biological roles. There remains limited evidence, however, whether dual inhibitors are truly optimal in terms of efficacy, safety and biological activity, or whether PTPN2 specific inhibitors should be pursued. Our aim was thus to systematically investigate the role of these two phosphatases in T-cell responses and tumor immune escape, to further refine the use of PTPN1/2 inhibitors as a therapeutic modality against cancer. We found that in CD8+ T cells, PTPN2 is the major player in limiting cytotoxic activity against cancer cells. However, PTPN2 deletion alone shows only a modest increase in cytotoxicity and is accompanied by a compensatory enhancement of PTPN1 protein levels. Additional deletion of PTPN1 in PTPN2 deficient T cells (dKO) is required for maximal cytotoxic activity and for the establishment of a distinct T cell memory subcluster capable of resisting canonical exhaustion. On the tumor side, the deletion of both phosphatases results in the synergistic augmentation of CXCL9, a potent CD8+ T cell chemoattractant. Using various cancer models, we demonstrate that cancers insensitive to checkpoint blockade are made vulnerable to immunotherapy by PTPN1/2 inhibition. Dual PTPN1/2 inhibitors achieve this effect through distinct cancer cell and T cell-specific effects that act in a complementary manner to checkpoint blockade. We are now pursuing the development of our lead PTPN1/2 inhibitor in clinical trials for the treatment of solid malignancies. Citation Format: Alexandre Poirier, Luis-Alberto Perez-Quintero, Erika Walback, Rui Su, Chenyue Wu, Michel L. Tremblay.. PTPN1/2 dual inhibition sensitizes solid tumors to checkpoint blockade immunotherapy by enhancing T cell cytotoxicity and by decreasing cancer cell immune evasion. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2166.