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Updated: Aug 22, 2025

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Enhanced T cell effector activity by targeting the Mediator kinase module

Katherine A Freitas1,2, Julia A Belk3, Elena Sotillo2

  • 1Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.

Science (New York, N.Y.)
|November 10, 2022
PubMed

Insights

Researchers identified MED12 and CCNC as key genes limiting T cell function in cancer immunotherapy. Deleting MED12 boosts antitumor activity, offering a new target for enhancing T cell responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cancer Research

Background:

  • T cells are crucial for cancer regression.
  • Identifying factors limiting T cell function is vital for improving immunotherapies.

Purpose of the Study:

  • To identify genes that limit T cell function in engineered T cells.
  • To explore the role of the Mediator kinase module in T cell effector programming.

Main Methods:

  • Genome-wide CRISPR knockout screens were performed in human chimeric antigen receptor (CAR) T cells.
  • MED12 and CCNC were identified as top hits limiting T cell function.
  • Targeted MED12 deletion and CDK8/19 kinase inhibition were investigated.

Main Results:

  • Targeted MED12 deletion enhanced antitumor activity and sustained effector phenotype in engineered T cells.
  • Inhibition of CDK8/19 kinase activity increased non-engineered T cell expansion.
  • MED12-deficient T cells showed increased Mediator chromatin occupancy and IL2RA expression.

Conclusions:

  • The Mediator kinase module plays a significant role in T cell effector programming.
  • Targeting MED12 and related kinases presents a promising strategy for enhancing antitumor T cell potency.

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