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An NK-like CAR T cell transition in CAR T cell dysfunction.
- Source :
-
Cell . Dec2021, Vol. 184 Issue 25, p6081-6081. 1p. - Publication Year :
- 2021
-
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. [Display omitted] • CAR T cells under chronic antigen stimulation show hallmarks of T cell exhaustion • CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition • CAR T cells with NK-like transition were identified in patients after treatment • Unlike WT CAR T cells, ID3 and SOX4 knockout CAR T cells retain anti-tumor immunity Continuous antigen exposure drives CAR T cell exhaustion and promotes CD8+ T-to-NK-like T cell transition. Transcription factors ID3 and SOX4 are upregulated during CAR dysfunction and regulate genes associated with exhaustion, including NK receptors. Knocking out ID3 and SOX4 in CAR T cells slows dysfunction and improves anti-tumor immunity. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CHIMERIC antigen receptors
*AUTOMOBILES
*PATIENT-ventilator dyssynchrony
Subjects
Details
- Language :
- English
- ISSN :
- 00928674
- Volume :
- 184
- Issue :
- 25
- Database :
- Academic Search Index
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 153974953
- Full Text :
- https://doi.org/10.1016/j.cell.2021.11.016