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Targeting PTPN2 enhances human CAR T cell efficacy and the development of long-term memory in mouse xenograft models.

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Title: Targeting PTPN2 enhances human CAR T cell efficacy and the development of long-term memory in mouse xenograft models.
Authors: Du, Xin, Goh, Pei K., Ma, Chenkai, Coughlan, Eamon, Greatorex, Spencer, Porter, Laura H., Russ, Brendan, Cummins, Katherine D., Sek, Kevin, Slaney, Clare Y., Scott, Andrew M., Oliaro, Jane, Neeson, Paul J., Risbridger, Gail P., Taylor, Renea A., Trapani, Joseph A., Turner, Stephen J., Darcy, Phillip K., Wiede, Florian, Tiganis, Tony
Source: Science Translational Medicine; 10/29/2025, Vol. 17 Issue 822, p1-19, 19p
Subject Terms: CHIMERIC antigen receptors, PROTEIN-tyrosine phosphatase, TUMOR microenvironment, IMMUNOLOGIC memory, GENOME editing, TUMORS, XENOGRAFTS, CYTOKINES
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. Editor's summary: Chimeric antigen receptor (CAR) T cell therapies have been much less successful against solid tumors than they have against hematological malignancies. To improve efficacy, Du and colleagues targeted protein tyrosine phosphatase N2 (PTPN2), an enzyme that plays an important role in maintaining T cell tolerance, through gene editing or through small-molecule inhibition, in human CAR T cells specific for the Lewis Y neoantigen. Targeting PTPN2 enhanced the activation and cytotoxicity of the CAR T cells, suppressing tumor growth and prolonging survival in several mouse models of epithelial cancers. Successful treatment was associated with the generation and intratumoral accumulation of stem cell memory–like CD8+ CAR T cells, altogether suggesting that targeting PTPN2 in CAR T cells may improve treatment response in patients with solid tumors. —Melissa L. Norton [ABSTRACT FROM AUTHOR]
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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<sup>+</sup> CAR T cells in tumor-bearing mice revealed that PTPN2 deficiency favored the generation of CD45RA<sup>+</sup> 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<sup>+</sup> CAR T cells and the overall persistence of CD8<sup>+</sup> 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. Editor's summary: Chimeric antigen receptor (CAR) T cell therapies have been much less successful against solid tumors than they have against hematological malignancies. To improve efficacy, Du and colleagues targeted protein tyrosine phosphatase N2 (PTPN2), an enzyme that plays an important role in maintaining T cell tolerance, through gene editing or through small-molecule inhibition, in human CAR T cells specific for the Lewis Y neoantigen. Targeting PTPN2 enhanced the activation and cytotoxicity of the CAR T cells, suppressing tumor growth and prolonging survival in several mouse models of epithelial cancers. Successful treatment was associated with the generation and intratumoral accumulation of stem cell memory–like CD8<sup>+</sup> CAR T cells, altogether suggesting that targeting PTPN2 in CAR T cells may improve treatment response in patients with solid tumors. —Melissa L. Norton [ABSTRACT FROM AUTHOR]
ISSN:19466234
DOI:10.1126/scitranslmed.adk0627