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

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

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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