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

Affiliations

• Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
• Innovation Research Center for Biofuture Technology (B-IRC), Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
• ImmmunoBiome Inc, Pohang, 37673, Republic of Korea.
• School of Life Science & Technology, ShanghaiTech University, Shanghai, 201210, China.
• Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
• Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
• Institute for Bioinformatics and Medical Informatics, University of Tübingen, Sand 14, Tübingen, 72076, Germany.
• International Max Planck Research School "From Molecules to Organisms", Max Planck Institute for Biology Tübingen, Max-Planck-Ring 5, Tübingen, 72076, Germany.
• Daehang Hospital, Seoul, 06699, Republic of Korea.
• Department of Surgery, Korea University College of Medicine, Seoul, 02841, Republic of Korea.
• State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology Chinese Academy of Sciences, Beijing, 100101, China.
• Lipidall Technologies Company Limited, Changzhou, 213022, Jiangsu Province, China.
• University of Chinese Academy of Sciences, Beijing, 100101, China.
• Center for Health Science and Technology, JIS Institute of Advanced Studies and Research, JIS University, Kolkata, 700091, India.
• Department of Microbiology, College of Natural Sciences, Dankook University, Cheonan, 31116, Republic of Korea.
• Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea. iimsh@postech.ac.kr.
• ImmmunoBiome Inc, Pohang, 37673, Republic of Korea. iimsh@postech.ac.kr.
• Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul, 03722, Republic of Korea. iimsh@postech.ac.kr.
• Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea. drudra@shanghaitech.edu.cn.
• School of Life Science & Technology, ShanghaiTech University, Shanghai, 201210, China. drudra@shanghaitech.edu.cn.

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.

调节性T细胞（Tregs）可建立显性免疫耐受，但会阻碍肿瘤免疫监视，因此有必要从特异性机理角度深入了解肿瘤浸润性 Tregs（TIL-Tregs）的功能。我们的研究表明，细胞因子翻译后O-连接的N-乙酰葡糖胺修饰（O-GlcNAcylation）的增强是促进肿瘤特异性基因表达特征的分子特征，也是区分TIL-Tregs与全身性TIL-Tregs的分子特征。我们发现，通过葡萄糖转运体 Glut3 改变葡萄糖利用是这一过程的主要促进因素。肿瘤浸润特异性地缺失 Glut3 会削弱肿瘤免疫耐受，而小鼠体内的稳态免疫稳态基本不受影响。此外，通过使用小鼠肿瘤模型和人类临床数据，我们发现 NF-κB 亚基 c-Rel 是这样一种因子，它通过 Glut3 依赖性 O-GlcNAcylation 在功能上协调肿瘤部位 Tregs 的基因表达。总之，这些结果不仅确定了免疫代谢改变和分子事件，这些改变和事件有助于Treg生物学的基本方面，特别是在肿瘤部位，而且还揭示了肿瘤特异性细胞特性，有助于开发以Treg为靶点的癌症免疫疗法。

关键词：Glut3，O-GlcNAcylation，调节性T细胞，Treg，GK1.5，53-6.72，PC61/PC61.5.3，XMG1.2，11B11，佰乐博，佰乐博生物