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

Good, Charly R, Aznar, M Angela, Kuramitsu, Shunichiro, Samareh, Parisa, Agarwal, Sangya, Donahue, Greg, Ishiyama, Kenichi, Wellhausen, Nils, Rennels, Austin K, Ma, Yujie, Tian, Lifeng, Guedan, Sonia, Alexander, Katherine A, Zhang, Zhen, Rommel, Philipp C, Singh, Nathan, Glastad, Karl M, Richardson, Max W, Watanabe, Keisuke, Tanyi, Janos L, O’Hara, Mark H, Ruella, Marco, Lacey, Simon F, Moon, Edmund K, Schuster, Stephen J, Albelda, Steven M, Lanier, Lewis L, Young, Regina M, Berger, Shelley L, June, Carl H (December 2021) An NK-like CAR T cell transition in CAR T cell dysfunction. Cell, 184 (25). 6081-6100.e26. ISSN 0092-8674

PDF 10.1016.j.cell.2021.11.016.pdf - Published Version Download (19MB)

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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > neoplasms organism description > animal diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > drugs and therapies > Immunotherapy organism description > animal > mammal organism description > animal > mammal > rodent > mouse organism description > animal > mammal > rodent
CSHL Authors:	Alexander, Katherine
Communities:	CSHL labs > Alexander lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	December 2021
Date Deposited:	16 Jul 2024 15:32
Last Modified:	16 Jul 2024 15:32
PMCID:	PMC8827167
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41613

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