1. Multi-phenotype CRISPR-Cas9 Screen Identifies p38 Kinase as a Target for Adoptive Immunotherapies
- Author
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Christine M. Kariya, Li Jia, Tori N. Yamamoto, Shashank J. Patel, Devikala Gurusamy, Sri Krishna, Zhiya Yu, Arash Eidizadeh, Madhusudhanan Sukumar, Amanda N. Henning, Nicholas P. Restifo, Mary A. Black, Nikolaos Zacharakis, Jenny H. Pan, Suman K. Vodnala, Douglas C. Palmer, Robert L. Eil, and Rigel J. Kishton
- Subjects
0301 basic medicine ,Male ,Cancer Research ,DNA damage ,p38 mitogen-activated protein kinases ,T-Lymphocytes ,Regulator ,Melanoma, Experimental ,Receptors, Antigen, T-Cell ,Breast Neoplasms ,Biology ,Immunotherapy, Adoptive ,p38 Mitogen-Activated Protein Kinases ,03 medical and health sciences ,Mice ,0302 clinical medicine ,CRISPR ,Animals ,Mice, Knockout ,Kinase ,Cell Differentiation ,Phenotype ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Female ,NY-ESO-1 ,CRISPR-Cas Systems ,Genetic Engineering ,Genetic screen - Abstract
Summary 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.
- Published
- 2019