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

Devikala Gurusamy, Amanda N. Henning, Tori N. Yamamoto, Zhiya Yu, Nikolaos Zacharakis, Sri Krishna, Rigel J. Kishton, Suman K. Vodnala, Arash Eidizadeh, Li Jia, Christine M. Kariya, Mary A. Black, Robert Eil, Douglas C. Palmer, Jenny H. Pan, Madhusudhanan Sukumar, Shashank J. Patel, Nicholas P. Restifo

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 languageEnglish (US)
Pages (from-to)818-833.e9
JournalCancer Cell
Volume37
Issue number6
DOIs
StatePublished - Jun 8 2020
Externally publishedYes

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

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