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

Charly R. Good, M. Angela Aznar, Shunichiro Kuramitsu, Parisa Samareh, Sangya Agarwal, Greg Donahue, Kenichi Ishiyama, Nils Wellhausen, Austin K. Rennels, Yujie Ma, Lifeng Tian, Sonia Guedan, Katherine A. Alexander, Zhen Zhang, Philipp C. Rommel, Nathan Singh, Karl M. Glastad, Max W. Richardson, Keisuke Watanabe, Janos L. TanyiMark H. O'Hara, Marco Ruella, Simon F. Lacey, Edmund K. Moon, Stephen J. Schuster, Steven M. Albelda, Lewis L. Lanier, Regina M. Young, Shelley L. Berger, Carl H. June

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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 languageEnglish
Pages (from-to)6081-6100.e26
JournalCell
Volume184
Issue number25
DOIs
StatePublished - 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

Fingerprint

Dive into the research topics of 'An NK-like CAR T cell transition in CAR T cell dysfunction'. Together they form a unique fingerprint.

Cite this