Combined inhibition of homologous PTPN1 and PTPN2 is synergistic in enhancing CD8 T cell effector functions.

Perez-Quintero, L. A.; Martinez-Cordoba, Z.; Carli, C.; Poirier, A.; Kamyabiazar, S.; Feng, C.-H.; Pacis, A.; Zolotarov, Y.; Pike, K.-A.; Delisle, J.-S.; Tremblay, M. L.

doi:10.1101/2023.04.17.537264

bioRxiv · 10.1101/2023.04.17.537264

Combined inhibition of homologous PTPN1 and PTPN2 is synergistic in enhancing CD8 T cell effector functions.

Perez-Quintero, L. A.·Martinez-Cordoba, Z.·Carli, C.·Poirier, A.·Kamyabiazar, S.·Feng, C.-H.·Pacis, A.·Zolotarov, Y.·Pike, K.-A.·Delisle, J.-S.·Tremblay, M. L.

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Abstract

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.

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Perez-Quintero, L. A., Martinez-Cordoba, Z., Carli, C., Poirier, A., Kamyabiazar, S., Feng, C.-H., Pacis, A., Zolotarov, Y., Pike, K.-A., Delisle, J.-S., Tremblay, M. L.. 2023-04-18. Combined inhibition of homologous PTPN1 and PTPN2 is synergistic in enhancing CD8 T cell effector functions.. https://doi.org/10.1101/2023.04.17.537264

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