Enhanced T cell effector activity by targeting the Mediator kinase module

Science. 2022 Nov 11;378(6620):eabn5647. doi: 10.1126/science.abn5647. Epub 2022 Nov 11.

Abstract

T cells are the major arm of the immune system responsible for controlling and regressing cancers. To identify genes limiting T cell function, we conducted genome-wide CRISPR knockout screens in human chimeric antigen receptor (CAR) T cells. Top hits were MED12 and CCNC, components of the Mediator kinase module. Targeted MED12 deletion enhanced antitumor activity and sustained the effector phenotype in CAR- and T cell receptor-engineered T cells, and inhibition of CDK8/19 kinase activity increased expansion of nonengineered T cells. MED12-deficient T cells manifested increased core Meditator chromatin occupancy at transcriptionally active enhancers-most notably for STAT and AP-1 transcription factors-and increased IL2RA expression and interleukin-2 sensitivity. These results implicate Mediator in T cell effector programming and identify the kinase module as a target for enhancing potency of antitumor T cell responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclin C* / genetics
  • Cyclin-Dependent Kinase 8 / metabolism
  • Cyclin-Dependent Kinases / metabolism
  • Genetic Testing
  • Genome-Wide Association Study
  • Humans
  • Immunotherapy, Adoptive
  • Mediator Complex* / genetics
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Receptors, Chimeric Antigen*
  • T-Lymphocytes* / immunology
  • Transcription Factors / genetics

Substances

  • Cyclin-Dependent Kinase 8
  • Cyclin-Dependent Kinases
  • Mediator Complex
  • Transcription Factors
  • Receptors, Chimeric Antigen
  • MED12 protein, human
  • CCNC protein, human
  • Cyclin C