1. An NK-like CAR T cell transition in CAR T cell dysfunction
- Author
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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, and June, Carl H
- Subjects
Rare Diseases ,Genetics ,Gene Therapy ,Biotechnology ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,CD8-Positive T-Lymphocytes ,Cell Line ,Tumor ,HEK293 Cells ,Humans ,Immunotherapy ,Adoptive ,Inhibitor of Differentiation Proteins ,Male ,Mice ,Mice ,Knockout ,Mice ,Nude ,Mice ,SCID ,Neoplasm Proteins ,Pancreatic Neoplasms ,Receptors ,Chimeric Antigen ,SOXC Transcription Factors ,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 ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - 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.
- Published
- 2021