Abstract
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 microenvironment. 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-to-NK-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 CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.
Original language | English |
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Pages (from-to) | 6081-6100.e26 |
Journal | Cell |
Volume | 184 |
Issue number | 25 |
DOIs | |
State | Published - Dec 9 2021 |
Keywords
- CAR T cell
- ID3
- NK-like T cell
- SOX4
- T cell dysfunction
- T cell exhaustion
- cancer
- cell transfer therapy
- immunology
- immunotherapy
- pancreatic cancer
- single-cell RNA-seq