Targeting PTPN2 enhances human CAR T cell efficacy and the development of long-term memory in mouse xenograft models
- Author(s)
- Du, X; Goh, PK; Ma, C; Coughlan, E; Greatorex, S; Porter, LH; Russ, B; Cummins, KD; Sek, K; Slaney, CY; Scott, AM; Oliaro, J; Neeson, PJ; Risbridger, GP; Taylor, RA; Trapani, JA; Turner, SJ; Darcy, PK; Wiede, F; Tiganis, T;
- Details
- Publication Year 2025-10-29,Volume 17,Issue #822,Page eadk0627
- Journal Title
- Science Translational Medicine
- Publication Type
- Research article
- Abstract
- Chimeric antigen receptor (CAR) T cells have been ineffective against solid tumors, where the hostile tumor microenvironment limits CAR T cell function and persistence. Protein tyrosine phosphatase N2 (PTPN2) attenuates T cell receptor and cytokine signaling to maintain T cell tolerance. Here, we used CRISPR-Cas9 gene editing or an inhibitor to target PTPN2 in human CAR T cells specific for the Lewis Y (LeY) neoantigen, which is expressed in most epithelial tumors. Targeting PTPN2 increased CAR and cytokine signaling, including interferon signaling, and enhanced the antigen-induced expansion, activation, and cytotoxicity of anti-LeY CAR T cells in vitro and in vivo. The deletion of PTPN2 in CAR T cells repressed the growth of human tumor and patient-derived xenografts in mice, when compared with unedited CAR T cells, and prolonged mouse survival. The administration of inhibitor also enhanced the ability of α-LeY CAR T cells to repress tumor growth. Cellular indexing of transcriptomes and epitopes by sequencing analysis of splenic PTPN2-deficient CD8(+) CAR T cells in tumor-bearing mice revealed that PTPN2 deficiency favored the generation of CD45RA(+) CAR T cells expressing markers of long-lived stem cell memory (SCM) CAR T cells. Flow cytometric analysis reaffirmed that the deletion or inhibition of PTPN2 promoted the intratumoral accumulation of SCM CD8(+) CAR T cells and the overall persistence of CD8(+) CAR T cells. These data support the use of gene editing or small-molecule inhibitors targeting PTPN2 in human CAR T cells to treat solid tumors.
- Keywords
- Animals; Humans; *Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism/antagonists &; inhibitors; *Xenograft Model Antitumor Assays; Mice; *Immunologic Memory; *Receptors, Chimeric Antigen/metabolism/immunology; Immunotherapy, Adoptive; CRISPR-Cas Systems/genetics; Cell Line, Tumor; *T-Lymphocytes/immunology; CD8-Positive T-Lymphocytes/immunology
- Department(s)
- Laboratory Research; Haematology
- Publisher's Version
- https://doi.org/10.1126/scitranslmed.adk0627
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-12-04 05:58:02
Last Modified: 2025-12-04 05:59:00