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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 ( Ptpn22Δ/Δ ) 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  α -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.

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