Enhanced T cell effector activity by targeting the Mediator kinase module-Reference-Cited by-同舟云学术

Enhanced T cell effector activity by targeting the Mediator kinase module

Published:2022-11-11 Issue:6620 Volume:378 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Freitas Katherine A.¹²^ORCID,Belk Julia A.³^ORCID,Sotillo Elena²^ORCID,Quinn Patrick J.²^ORCID,Ramello Maria C.²,Malipatlolla Meena²,Daniel Bence⁴⁵^ORCID,Sandor Katalin⁵^ORCID,Klysz Dorota²^ORCID,Bjelajac Jeremy²⁶^ORCID,Xu Peng²,Burdsall Kylie A.²^ORCID,Tieu Victor⁷^ORCID,Duong Vandon T.⁷,Donovan Micah G.⁸^ORCID,Weber Evan W.²⁹^ORCID,Chang Howard Y.⁴⁹¹⁰^ORCID,Majzner Robbie G.²¹¹^ORCID,Espinosa Joaquin M.⁸¹²^ORCID,Satpathy Ansuman T.²⁵⁹^ORCID,Mackall Crystal L.²⁹¹¹¹³^ORCID

Affiliation:

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

2. Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.

3. Department of Computer Science, Stanford University, Stanford, CA, USA.

4. Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.

5. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

6. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.

7. Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, USA.

8. Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

9. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.

10. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.

11. Division of Pediatric Hematology/Oncology and Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.

12. Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

13. Division of Blood and Marrow Transplantation and Cell Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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