Chemical inhibition of DNA‐PKcs impairs the activation and cytotoxicity of CD4+ helper and CD8+ effector T cells

Abstract

AbstractModulation of T cell activity is an effective strategy for the treatment of autoimmune diseases, immune‐related disorders and cancer. This highlights a critical need for the identification of proteins that regulate T cell function. The kinase DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs) is emerging as a potent regulator of the immune system, spurring interest in its use as a therapeutic target. In murine models of immune‐related diseases including asthma and rheumatoid arthritis, treatment with small‐molecule DNA‐PKcs inhibitors decreased the disease severity. Additionally, DNA‐PKcs inhibitors reduced T cell‐mediated graft rejection in a murine allogenic skin graft model. These in vivo studies suggest the use of DNA‐PKcs inhibitors as immunotherapy for autoimmune and T cell‐mediated disorders. In this study, we sought to characterize further the effects of DNA‐PKcs inhibitors on T cells to better understand their clinical potential. We determined that inhibition of DNA‐PKcs using inhibitor NU7441 and the inhibitors currently in clinical trials for cancer therapy, M3184 and AZD7648, abrogated the activation of murine and human CD4+ and CD8+ T cells as evidenced by the reduced expression of the activation markers CD69 and CD25. Furthermore, inhibition of DNA‐PKcs impeded metabolic pathways and the proliferation of activated T cells. This reduced the ability of OTI‐CD8+ T cells to kill cancer cells and the expression of IFNγ and cytotoxic genes. These results highlight a critical role for DNA‐PKcs in T cells and validate future studies using DNA‐PKcs inhibitors as immune modulation therapy for the treatment of immune‐related diseases.