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

Wiede, F; Lu, KH; Du, X; Zeissig, MN; Xu, R; Goh, PK; Xirouchaki, CE; Hogarth, SJ; Greatorex, S; Sek, K; Daly, RJ; Beavis, PA; Darcy, PK; Tonks, NK; Tiganis, T

Author(s): Wiede, F; Lu, KH; Du, X; Zeissig, MN; Xu, R; Goh, PK; Xirouchaki, CE; Hogarth, SJ; Greatorex, S; Sek, K; Daly, RJ; Beavis, PA; Darcy, PK; Tonks, NK; Tiganis, T;
Details: Publication Year 2022-03-01,Volume 12,Issue #3,Page 752-773
Journal Title: Cancer Discovery
Publication Type: Research article
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. This article is highlighted in the In This Issue feature, p. 587.
Keywords: Animals; CD8-Positive T-Lymphocytes/metabolism; Cell Line, Tumor; Humans; Immunotherapy, Adoptive; Mice; *Neoplasms/metabolism; *Programmed Cell Death 1 Receptor/metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Xenograft Model Antitumor Assays
Department(s): Laboratory Research
PubMed ID: 34794959
Publisher's Version: https://doi.org/10.1158/2159-8290.CD-21-0694
Open Access at Publisher's Site: https://doi.org/10.1158/2159-8290.Cd-21-0694
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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Last Modified: 2025-05-09 07:33:16