An NK-like CAR T cell transition in CAR T cell dysfunction
| Autor: | Keisuke Watanabe, Charly R. Good, Kenichi Ishiyama, Greg Donahue, Marco Ruella, Lewis L. Lanier, Simon F. Lacey, Nathan Singh, Janos L. Tanyi, Austin K. Rennels, Shunichiro Kuramitsu, Yujie Ma, Lifeng Tian, Shelley L. Berger, Karl M. Glastad, Mark H. O'Hara, Regina M. Young, Parisa Samareh, Zhen Zhang, Edmund K. Moon, Carl H. June, M. Angela Aznar, Philipp C. Rommel, Steven M. Albelda, Katherine A. Alexander, Sangya Agarwal, Stephen J. Schuster, Max W. Richardson, Nils Wellhausen, Sonia Guedan |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
medicine.medical_treatment T-Lymphocytes Mice Nude Mice SCID Biology CD8-Positive T-Lymphocytes Immunotherapy Adoptive General Biochemistry Genetics and Molecular Biology Article SOXC Transcription Factors SOX4 Mice Antigen Cell Line Tumor Cell transfer therapy medicine Animals Humans Transcription factor Fatigue Mice Knockout Receptors Chimeric Antigen T-cell receptor Immunotherapy Chimeric antigen receptor Neoplasm Proteins Killer Cells Natural Pancreatic Neoplasms Phenotype HEK293 Cells Cancer research Inhibitor of Differentiation Proteins human activities CD8 |
| Zdroj: | Cell |
| ISSN: | 1097-4172 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|