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 (November 2021) PTP1B is an intracellular checkpoint that limits T cell and CAR T cell anti-tumor immunity. Cancer Discovery. ISSN 2159-8274
Abstract
Immunotherapies aimed at alleviating the inhibitory constraints on Tcells have revolutionised 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 the increased PTP1B limits T cell expansion and cytotoxicity to contribute to tumor growth. T cell-specific PTP1B deletion increased STAT-5 signaling and this enhanced the antigen-induced expansion and cytotoxicity of CD8+ T cells to suppress tumor growth. The pharmacological 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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells |
| CSHL Authors: | |
| Communities: | CSHL labs > Tonks lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 18 November 2021 |
| Date Deposited: | 06 Dec 2021 14:45 |
| Last Modified: | 11 Mar 2022 15:29 |
| PMCID: | PMC8904293 |
| URI: | https://repository.cshl.edu/id/eprint/40431 |
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