2. Academic Validation
  3. A deubiquitination module essential for Treg fitness in the tumor microenvironment

A deubiquitination module essential for Treg fitness in the tumor microenvironment

  • Sci Adv. 2022 Nov 25;8(47):eabo4116. doi: 10.1126/sciadv.abo4116.
Elena Montauti 1,  Samuel E Weinberg 1,  Peng Chu 2,  Shuvam Chaudhuri 1,  Nikita L Mani 1,  Radhika Iyer 1,  Yuanzhang Zhou 2,  Yusi Zhang 3,  Changhong Liu 4,  Chen Xin 5,  Shana Gregory 1,  Juncheng Wei 1,  Yana Zhang 1,  Wantao Chen 6,  Zhaolin Sun 2,  Ming Yan 1 6,  Deyu Fang 1
Affiliations

Affiliations

  • 1 Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL 60611, USA.
  • 2 Department of Pharmacology, Dalian Medical University, Dalian 116044, China.
  • 3 Department of Immunology, The Fourth Military Medical University, Xi'an 710032, China.
  • 4 Department of Thoracic Surgery, The Second Hospital of Dalian Medical University, Dalian 116021, China.
  • 5 Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian 116021, China.
  • 6 Department of Oral Maxillofacial Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, China.
PMID: 36427305 DOI: 10.1126/sciadv.abo4116
Abstract

The tumor microenvironment (TME) enhances regulatory T (Treg) cell stability and immunosuppressive functions through up-regulation of lineage transcription factor Foxp3, a phenomenon known as Treg fitness or adaptation. Here, we characterize previously unknown TME-specific cellular and molecular mechanisms underlying Treg fitness. We demonstrate that TME-specific stressors including transforming growth factor-β (TGF-β), hypoxia, and nutrient deprivation selectively induce two Foxp3-specific deubiquitinases, Ubiquitin-Specific Peptidase 22 (Usp22) and Usp21, by regulating TGF-β, HIF, and mTOR signaling, respectively, to maintain Treg fitness. Simultaneous deletion of both USPs in Treg cells largely diminishes TME-induced Foxp3 up-regulation, alters Treg metabolic signatures, impairs Treg-suppressive function, and alleviates Treg suppression on cytotoxic CD8+ T cells. Furthermore, we developed the first Usp22-specific small-molecule inhibitor, which dramatically reduced intratumoral Treg Foxp3 expression and consequently enhanced antitumor immunity. Our findings unveil previously unappreciated mechanisms underlying Treg fitness and identify Usp22 as an antitumor therapeutic target that inhibits Treg adaptability in the TME.

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