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

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

Automated summary

CAR T cell therapy has achieved success in hematological malignancies but faces challenges in solid tumors due to CAR T cell exhaustion. Dysfunction of CAR T cells in solid tumors is associated with CD8+ T-to-NK-like T cell transition, and genetic downregulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy.