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

Cell. 2021 Dec 9;184(25):6081-6100.e26. doi: 10.1016/j.cell.2021.11.016. Epub 2021 Dec 2.


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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Inhibitor of Differentiation Proteins / immunology
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Mice, SCID
  • Neoplasm Proteins / immunology
  • Pancreatic Neoplasms / therapy*
  • Receptors, Chimeric Antigen / immunology*
  • SOXC Transcription Factors / immunology


  • Inhibitor of Differentiation Proteins
  • Neoplasm Proteins
  • Receptors, Chimeric Antigen
  • SOX4 protein, human
  • SOXC Transcription Factors
  • ID3 protein, human