Mediator complex subunit 1 architects a tumorigenic Treg cell program independent of inflammation

Shuvam M. Chaudhuri, Samuel E. Weinberg, Dongmei Wang, Lenore K. Yalom, Elena Montauti, Radhika Iyer, Amy Y. Tang, Manuel A. Torres Acosta, Jian Shen, Nikita L. Mani, Shengnan Wang, Kun Liu, Weiyuan Lu, Triet M. Bui, Laura D. Manzanares, Zeinab Dehghani, Ching Man Wai, Beixue Gao, Juncheng Wei, Feng YueWeiguo Cui, Benjamin D. Singer, Ronen Sumagin, Yana Zhang, Deyu Fang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

While immunotherapy has revolutionized cancer treatment, its safety has been hampered by immunotherapy-related adverse events. Unexpectedly, we show that Mediator complex subunit 1 (MED1) is required for T regulatory (Treg) cell function specifically in the tumor microenvironment. Treg cell-specific MED1 deletion does not predispose mice to autoimmunity or excessive inflammation. In contrast, MED1 is required for Treg cell promotion of tumor growth because MED1 is required for the terminal differentiation of effector Treg cells in the tumor. Suppression of these terminally differentiated Treg cells is sufficient for eliciting antitumor immunity. Both human and murine Treg cells experience divergent paths of differentiation in tumors and matched tissues with non-malignant inflammation. Collectively, we identify a pathway promoting the differentiation of a Treg cell effector subset specific to tumors and demonstrate that suppression of a subset of Treg cells is sufficient for promoting antitumor immunity in the absence of autoimmune consequences.

Original languageEnglish (US)
Article number101441
JournalCell Reports Medicine
Volume5
Issue number3
DOIs
StatePublished - Mar 19 2024

Funding

We thank members of the Fang Laboratory for technical advice and discussion. We thank Dr. Jindan Yu and Dr. Bin Zhang for supplying tumor cell lines. This work was supported by the Northwestern University RHLCCC Flow Cytometry Facility and a Cancer Center Support Grant (NCI CA060553). Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by (NCI P30-CA060553) awarded to the Robert H. Lurie Comprehensive Cancer Center. The single-cell library preparation and sequencing was done at Northwestern University NUseq facility core with the support of NIH Grant (1S10OD025120). S.M.C. was supported by T32DK007169. M.A.T. was supported by T32HL076139. B.D.S. was supported by R01HL149883, R01HL153122, P01HL154998, and U19AI135964. R.S. was supported by the Crohn's & Colitis Foundation Senior Research Award, R01DK124199, and RO1AI153568. D.F. was supported by R01CA257520, R01CA232347, R01DK126908, and R01DK120330. Conceptualization: S.M.C. S.E.W. and D.F.; methodology, S.M.C. Y.Z. S.E.W. and D.F.; investigation, S.M.C. Y.Z, E.M. L.Y. R.I. A.T. M,A,T. N.M. S.W. K.L. W.L. T.M.B. Z.D. L.M. C.W. B.G. J.W. R.S. and S.E.W.; formal analysis, S.M.C. Y.Z. D.W. and J.S.; writing – original draft, S.M.C; writing – review & and editing, S.M.C. S.E.W. and D.F.; funding acquisition, F.Y. W.C. B.D.S. R.S. and D.F.; supervision, D.F. B.D.S. holds United States Patent No. US 10,905,706 B2, “Compositions and Methods to Accelerate Resolution of Acute Lung Inflammation” and serves on the Scientific Advisory Board of Zoe Biosciences, outside of the submitted work. We thank members of the Fang Laboratory for technical advice and discussion. We thank Dr. Jindan Yu and Dr. Bin Zhang for supplying tumor cell lines. This work was supported by the Northwestern University RHLCCC Flow Cytometry Facility and a Cancer Center Support Grant ( NCI CA060553 ). Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by ( NCI P30-CA060553 ) awarded to the Robert H. Lurie Comprehensive Cancer Center . The single-cell library preparation and sequencing was done at Northwestern University NUseq facility core with the support of NIH Grant ( 1S10OD025120 ). S.M.C. was supported by T32DK007169 . M.A.T. was supported by T32HL076139 . B.D.S. was supported by R01HL149883 , R01HL153122 , P01HL154998 , and U19AI135964 . R.S. was supported by the Crohn’s & Colitis Foundation Senior Research Award, R01DK124199 , and RO1AI153568 . D.F. was supported by R01CA257520 , R01CA232347 , R01DK126908 , and R01DK120330 .

Keywords

  • ATAC-seq
  • FOXP3
  • MED1
  • autoimmunity
  • differentiation
  • scRNA-seq
  • tumor T regulatory cell
  • tumor immunology

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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