PTP1B Is an Intracellular Checkpoint that Limits T-cell and CAR T-cell Antitumor Immunity.

Cancer discovery 2022 Mar 01

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Immunotherapies aimed at alleviating the inhibitory constraints on T cells have revolutionized cancer management. To date, these have focused on the blockade of cell-surface checkpoints such as PD-1. Herein we identify protein tyrosine phosphatase 1B (PTP1B) as an intracellular checkpoint that is upregulated in T cells in tumors. We show that increased PTP1B limits T-cell expansion and cytotoxicity to contribute to tumor growth. T cell-specific PTP1B deletion increased STAT5 signaling, and this enhanced the antigen-induced expansion and cytotoxicity of CD8+ T cells to suppress tumor growth. The pharmacologic inhibition of PTP1B recapitulated the T cell-mediated repression of tumor growth and enhanced the response to PD-1 blockade. Furthermore, the deletion or inhibition of PTP1B enhanced the efficacy of adoptively transferred chimeric antigen receptor (CAR) T cells against solid tumors. Our findings identify PTP1B as an intracellular checkpoint whose inhibition can alleviate the inhibitory constraints on T cells and CAR T cells to combat cancer. Tumors subvert antitumor immunity by engaging checkpoints that promote T-cell exhaustion. Here we identify PTP1B as an intracellular checkpoint and therapeutic target. We show that PTP1B is upregulated in intratumoral T cells and that its deletion or inhibition enhances T-cell antitumor activity and increases CAR T-cell effectiveness against solid tumors. This article is highlighted in the In This Issue feature, p. 587. ©2021 The Authors; Published by the American Association for Cancer Research.

Citation

Florian Wiede, Kun-Hui Lu, Xin Du, Mara N Zeissig, Rachel Xu, Pei Kee Goh, Chrysovalantou E Xirouchaki, Samuel J Hogarth, Spencer Greatorex, Kevin Sek, Roger J Daly, Paul A Beavis, Phillip K Darcy, Nicholas K Tonks, Tony Tiganis. PTP1B Is an Intracellular Checkpoint that Limits T-cell and CAR T-cell Antitumor Immunity. Cancer discovery. 2022 Mar 01;12(3):752-773