Journal
CANCER CELL
Volume 37, Issue 6, Pages 818-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2020.05.004
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Funding
- Intramural Research Program of the NCI
- Cancer Moonshot program for the Center for Cell-based Therapy at the NCI, NIH
- Milken Family Foundation
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T cells are central to all currently effective cancer immunotherapies, but the characteristics defining therapeutically effective anti-tumor T cells have not been comprehensively elucidated. Here, we delineate four phenotypic qualities of effective anti-tumor T cells: cell expansion, differentiation, oxidative stress, and genomic stress. Using a CRISPR-Cas9-based genetic screen of primary T cells we measured the multi-phenotypic impact of disrupting 25 T cell receptor-driven kinases. We identified p38 kinase as a central regulator of all four phenotypes and uncovered transcriptional and antioxidant pathways regulated by p38 in T cells. Pharmacological inhibition of p38 improved the efficacy of mouse anti-tumor T cells and enhanced the functionalities of human tumor-reactive and gene-engineered T cells, paving the way for clinically relevant interventions.
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