An NK-like CAR T cell transition in CAR T cell dysfunction

Abstract

Chimeric antigen receptor (CAR) Tcell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR Tcell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR Tcells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of Tcell exhaustion and discover, both invitro and in CAR Tcell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like Tcell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR Tcell exhaustion. Our findings shed light on the plasticity of human CAR Tcells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR Tcell therapy in solid tumors by preventing or delaying CAR Tcell dysfunction.