2. Academic Validation
  3. Glut3 promotes cellular O-GlcNAcylation as a distinctive tumor-supportive feature in Treg cells

Glut3 promotes cellular O-GlcNAcylation as a distinctive tumor-supportive feature in Treg cells

  • Cell Mol Immunol. 2024 Dec;21(12):1474-1490. doi: 10.1038/s41423-024-01229-8.
Amit Sharma 1 2,  Garima Sharma # 1 3,  Zhen Gao # 4,  Ke Li 4,  Mutong Li 4,  Menglin Wu 4,  Chan Johng Kim 1 5,  Yingjia Chen 6,  Anupam Gautam 7 8,  Hong Bae Choi 9,  Jin Kim 10,  Jung-Myun Kwak 10,  Sin Man Lam 11 12,  Guanghou Shui 11 13,  Sandip Paul 14,  Yongqiang Feng 6,  Keunsoo Kang 15,  Sin-Hyeog Im 16 17 18,  Dipayan Rudra 19 20
Affiliations

Affiliations

  • 1 Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
  • 2 Innovation Research Center for Biofuture Technology (B-IRC), Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
  • 3 ImmmunoBiome Inc, Pohang, 37673, Republic of Korea.
  • 4 School of Life Science & Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 5 Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • 6 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 7 Institute for Bioinformatics and Medical Informatics, University of Tübingen, Sand 14, Tübingen, 72076, Germany.
  • 8 International Max Planck Research School "From Molecules to Organisms", Max Planck Institute for Biology Tübingen, Max-Planck-Ring 5, Tübingen, 72076, Germany.
  • 9 Daehang Hospital, Seoul, 06699, Republic of Korea.
  • 10 Department of Surgery, Korea University College of Medicine, Seoul, 02841, Republic of Korea.
  • 11 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology Chinese Academy of Sciences, Beijing, 100101, China.
  • 12 Lipidall Technologies Company Limited, Changzhou, 213022, Jiangsu Province, China.
  • 13 University of Chinese Academy of Sciences, Beijing, 100101, China.
  • 14 Center for Health Science and Technology, JIS Institute of Advanced Studies and Research, JIS University, Kolkata, 700091, India.
  • 15 Department of Microbiology, College of Natural Sciences, Dankook University, Cheonan, 31116, Republic of Korea.
  • 16 Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea. iimsh@postech.ac.kr.
  • 17 ImmmunoBiome Inc, Pohang, 37673, Republic of Korea. iimsh@postech.ac.kr.
  • 18 Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul, 03722, Republic of Korea. iimsh@postech.ac.kr.
  • 19 Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea. drudra@shanghaitech.edu.cn.
  • 20 School of Life Science & Technology, ShanghaiTech University, Shanghai, 201210, China. drudra@shanghaitech.edu.cn.
  • # Contributed equally.
PMID: 39468304 DOI: 10.1038/s41423-024-01229-8
Abstract

Regulatory T cells (Tregs) establish dominant immune tolerance but obstruct tumor immune surveillance, warranting context-specific mechanistic insights into the functions of tumor-infiltrating Tregs (TIL-Tregs). We show that enhanced posttranslational O-linked N-acetylglucosamine modification (O-GlcNAcylation) of cellular factors is a molecular feature that promotes a tumor-specific gene expression signature and distinguishes TIL-Tregs from their systemic counterparts. We found that altered glucose utilization through the glucose transporter GLUT3 is a major facilitator of this process. Treg-specific deletion of GLUT3 abrogates tumor immune tolerance, while steady-state immune homeostasis remains largely unaffected in mice. Furthermore, by employing mouse tumor models and human clinical data, we identified the NF-κB subunit c-Rel as one such factor that, through Glut3-dependent O-GlcNAcylation, functionally orchestrates gene expression in Tregs at tumor sites. Together, these results not only identify immunometabolic alterations and molecular events contributing to fundamental aspects of Treg biology, specifically at tumor sites but also reveal tumor-specific cellular properties that can aid in the development of Treg-targeted Cancer immunotherapies.

Keywords

Glut3; O-GlcNAcylation; Regulatory T cells; Treg; Treg metabolism.

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