Molecular and cellular biologyJan 18, 2022

Blocking Protein Tyrosine Phosphatase 22 Does Not Improve CAR T Cell Therapy Against Solid Tumors

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 2, 2026

Abstract

PTPN22 deficiency does not enhance the antitumor activity of CAR T cells in solid organ malignancies.

Adoptive cell therapy using CAR T cells has shown success in treating certain B cell cancers but struggles with solid tumors.
Targeting negative regulators of T cell signaling, such as PTPN22, has been explored to improve CAR T cell efficacy.
PTPN22 deficiency was associated with stronger effector T cell responses and reduced tumor growth in syngeneic models.
Despite these responses, PTPN22 deficiency did not improve the effectiveness of CAR T cells targeting the HER2 oncoprotein.
The lack of enhanced cytotoxic activity was also observed for human CAR T cells targeting the Lewis Y antigen.

Simplified

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 () mice (C57BL/6) and assessed the impact of PTPN22 deficiency on the cytotoxicity and efficacy of CAR T cellsand. As reported previously, PTPN22 deficiency was accompanied by the promotion of effector T cell responsesand the repression of syngeneic tumor growth. However, PTPN22 deficiency did not enhance the cytotoxic activity of murine CAR T cells targeting the extracellular domain of the human oncoprotein HER2. Moreover, PTPN22-deficient α-HER2 CAR T cells or ovalbumin-specific OT-I CD8T cells adoptively transferred into mice bearing HER2mammary 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. Ptpn22in vitro in vivo ex vivo in vivo in vitro Δ/Δ + +

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Blocking Protein Tyrosine Phosphatase 22 Does Not Improve CAR T Cell Therapy Against Solid Tumors

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