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 th...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.展开更多
基金YC was financially supported by the Dissertation Completion Award of the University of Georgia and American Lebanese Syrian Associated Charities(ALSAC)at St.Jude Children’s Research HospitalAG acknowledges support by the High Performance and Cloud Computing Group at the Zentrum für Datenverarbeitung of the University of Tübingen,the state of Baden-Württemberg through bwHPC and the German Research Foundation(DFG)through grant no INST 37/935-1 FUGG,and the de.NBI Cloud within the German Network for Bioinformatics Infrastructure(de.NBI)and ELIXIR-DE(Forschungszentrum Jülich and W-de.NBI-001,W-de.NBI-004,W-de.NBI-008,W-de.NBI-010,W-de.NBI-013,W-de.NBI-014,W-de.NBI-016,W-de.NBI-022)for supporting the computational analysis carried out in this work.AS was supported by BrainKorea21 Plus scholarship from the National Research Foundation of Korea(NRF)+1 种基金This research,in part,was supported by the Basic Science Research Program(grant#4.24643.01)funded by the Ministry of Education,Korea,and NRF grants#RS-2023-00260454(AS)and RS-2024-00345575(SHI)funded by the Korea Ministry of Science and ICT(MSIT)DR is recipient of National Natural Science Foundation of China grant#32470980.
文摘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.
