Abstract
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.
Original language | English (US) |
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Pages (from-to) | 818-833.e9 |
Journal | Cancer Cell |
Volume | 37 |
Issue number | 6 |
DOIs | |
State | Published - Jun 8 2020 |
Externally published | Yes |
Keywords
- CD19 CAR T cell
- CRISPR-Cas9 screen
- DNA damage
- NY-ESO-1
- ROS
- adoptive transfer immunotherapy
- differentiation
- multi-phenotype
- neoantigen TIL
- p38
ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research