CRISPR-mediated deletion of the Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) improves human T cell function for adoptive T cell therapy

Abstract

Adoptive T cell transfer has improved the treatment of cancer patients. However, treatment of solid tumors is still challenging and new strategies that optimize T cell function and response duration in the tumor could be beneficial additions to cancer therapy. In this study, we deleted the intracellular phosphatase PTPN22 and the endogenous TCR chain from human PBMC-derived T cells using CRISPR/Cas9 and transduced them with TCRs specific for a defined antigen. Deletion of PTPN22 in human T cells increased the secretion of IFN{gamma} and GM-CSF in multiple donors. The cells retained a polyfunctional cytokine expression after re-stimulation and greater numbers of PTPN22KO T cells expressed inflammatory cytokines compared to unmutated control cells. PTPN22KO T cells seemed to be more polyfunctional at low antigen concentrations. Additionally, we were able to show that that PTPN22KO T cells were more effective in controlling tumor cell growth. This suggests that they might be more functional within the suppressive tumor microenvironment thereby overcoming the limitations of immunotherapy for solid tumors.