Multi-phenotype CRISPR-Cas9 Screen Identifies p38 Kinase as a Target for Adoptive Immunotherapies

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...

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Bibliographic Details
Published in:Cancer cell 2020-06, Vol.37 (6), p.818-833.e9
Main Authors: Gurusamy, Devikala, Henning, Amanda N., Yamamoto, Tori N., Yu, Zhiya, Zacharakis, Nikolaos, Krishna, Sri, Kishton, Rigel J., Vodnala, Suman K., Eidizadeh, Arash, Jia, Li, Kariya, Christine M., Black, Mary A., Eil, Robert, Palmer, Douglas C., Pan, Jenny H., Sukumar, Madhusudhanan, Patel, Shashank J., Restifo, Nicholas P.
Format: Article
Language:English
Subjects:
adoptive transfer immunotherapy
Animals
Breast Neoplasms - immunology
Breast Neoplasms - pathology
Breast Neoplasms - therapy
CD19 CAR T cell
Cell Differentiation
CRISPR-Cas Systems
CRISPR-Cas9 screen
differentiation
DNA damage
Female
Genetic Engineering
Immunotherapy, Adoptive - methods
Male
Melanoma, Experimental - immunology
Melanoma, Experimental - pathology
Melanoma, Experimental - therapy
Mice
Mice, Inbred C57BL
Mice, Knockout
multi-phenotype
neoantigen TIL
NY-ESO-1
p38
p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases - genetics
Phenotype
Receptors, Antigen, T-Cell - physiology
ROS
T-Lymphocytes - immunology
T-Lymphocytes - transplantation
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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. [Display omitted] •Expansion, memory, and oxidative and genomic stress define effective anti-tumor T cells•Multi-phenotype CRISPR-Cas9 screen reveals functional role of TCR-driven kinases•p38 regulates memory, redox homeostasis, and anti-tumor function of T cells•p38 is established as a target for improving TCR and CAR adoptive T cell therapies Gurusamy et al. identify phenotypes of effective anti-tumor T cells and reveal p38 as a central regulator of therapeutically desired T cell characteristics in a multi-phenotype screen. Inhibition of p38 promotes effective T cell phenotypes and enhances the anti-tumor efficacy of adoptive T cell immunotherapies.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccell.2020.05.004