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

• Published in: Cancer discovery Vol. 12; no. 3; pp. 752 - 773
• Main Authors: Wiede, Florian, Lu, Kun-Hui, Du, Xin, Zeissig, Mara N, Xu, Rachel, Goh, Pei Kee, Xirouchaki, Chrysovalantou E, Hogarth, Samuel J, Greatorex, Spencer, Sek, Kevin, Daly, Roger J, Beavis, Paul A, Darcy, Phillip K, Tonks, Nicholas K, Tiganis, Tony
• Format: Journal Article
• Language: English
• Published: United States 01.03.2022
• Subjects: 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
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-21-0694

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.