Targeting Protein Tyrosine Phosphatase 22 Does Not Enhance the Efficacy of Chimeric Antigen Receptor T Cells in Solid Tumors

Du, X; Darcy, PK; Wiede, F; Tiganis, T

Author(s): Du, X; Darcy, PK; Wiede, F; Tiganis, T;
Details: Publication Year 2022-03-17,Volume 42,Issue #3,Page e00449-21
Journal Title: Molecular and Cellular Biology
Publication Type: Research article
Abstract: Adoptive cell therapy with chimeric antigen receptor (CAR) T cells has revolutionized the treatment of certain B cell malignancies but has been in ineffective against solid tumors. Recent studies have highlighted the potential of targeting negative regulators of T cell signaling to enhance the efficacy and extend the utility of CAR T cells to solid tumors. Autoimmunity-linked protein tyrosine phosphatase N22 (PTPN22) has been proposed as a target for cancer immunotherapy. Here, we have used CRISPR/Cas9 gene editing to generate PTPN22-deficient (Ptpn22(Delta/Delta)) mice (C57BL/6) and assessed the impact of PTPN22 deficiency on the cytotoxicity and efficacy of CAR T cells in vitro and in vivo. As reported previously, PTPN22 deficiency was accompanied by the promotion of effector T cell responses ex vivo and the repression of syngeneic tumor growth in vivo. However, PTPN22 deficiency did not enhance the cytotoxic activity of murine CAR T cells targeting the extracellular domain of the human oncoprotein HER2 in vitro. Moreover, PTPN22-deficient alpha-HER2 CAR T cells or ovalbumin-specific OT-I CD8(+) T cells adoptively transferred into mice bearing HER2(+) mammary tumors or ovalbumin-expressing mammary or colorectal tumors, respectively, were no more effective than their wild-type counterparts in suppressing tumor growth. The deletion of PTPN22 using CRISPR/Cas9 gene editing also did not affect the cytotoxic activity of human CAR T cells targeting the Lewis Y antigen that is expressed by many human solid tumors. Therefore, PTPN22 deficiency does not enhance the antitumor activity of CAR T cells in solid organ malignancies.
Keywords: Animals; CD8-Positive T-Lymphocytes/metabolism; Cell Line, Tumor; *Immunotherapy, Adoptive; Mice; Mice, Inbred C57BL; *Neoplasms/genetics; Ovalbumin; *Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics; Receptors, Antigen, T-Cell/genetics; *Receptors, Chimeric Antigen/genetics/metabolism; Xenograft Model Antitumor Assays; CAR T cell; Ptpn22; T cell; immunotherapy; protein tyrosine phosphatase; tumor; tumor immunology
Department(s): Laboratory Research
PubMed ID: 35041491
Publisher's Version: https://doi.org/10.1128/MCB.00449-21
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-24 01:12:10

Last Modified: 2024-10-24 01:14:10