PTP1B is an intracellular checkpoint that limits T-cell and CAR T-cell antitumor immunity

F Wiede, KH Lu, X Du, MN Zeissig, R Xu, PK Goh… - Cancer Discovery, 2022 - AACR
Cancer Discovery, 2022AACR
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 …
Abstract
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.
Significance
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.
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