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4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8^(+) T cell proliferation

Cellular & Molecular Immunology 2017年第9期14卷 748-757页

作者： Beom K Choi Do Y Lee Don G Lee Young H Kim Seon-Hee Kim Ho S Oh chungyong han Byoung S Kwon Cancer Immunology Branch Division of Cancer BiologyNational Cancer CenterGoyangGyeonggi 10408Korea Department of Internal Medicine Yonsei University College of MedicineSeoul 120-752Korea Immune Cell Production Unit Program for Immunotherapeutic ResearchNational Cancer CenterGyeonggi 10408Korea Eutilex Catholic University School of MedicineSeoul 06591Korea Department of Medicine Tulane University Health Sciences CenterNew OrleansLA 70112USA

4-1BB(CD137)is a strong enhancer of the proliferation of CD8^(+)T *** these cells require increased production of energy and biomass to support their proliferation,we hypothesized that 4-1BB signaling activated glucose and fatty acid *** found that treatment with agonistic anti-4-1BB mAb promoted the proliferation of CD8^(+)T cells in vitro,increasing their size and *** with a glycolysis inhibitor and a fatty acid oxidation inhibitor revealed that CD8^(+)T cell proliferation required both glucose and fatty acid ***-4-1BB treatment increased glucose transporter 1 expression and activated the liver kinase B1(LKB1)-AMP-activated protein kinase(AMPK)-acetyl-CoA carboxylase(ACC)signaling pathway,which may be responsible for activating the metabolism of glucose and fatty *** also examined whether blocking glucose or fatty acid metabolism affected cell cycle progression and the anti-apoptotic effect of 4-1BB *** increase of anti-apoptotic factors and cyclins in response to anti-4-1BB treatment was completely prevented by treating CD8^(+)T cells with the fatty acid oxidation inhibitor,etomoxir,but not with the glycolysis inhibitor,*** conclude that anti-4-1BB treatment activates glucose and fatty acid metabolism thus supporting the increased demand for energy and biomass,and that fatty acid metabolism plays a crucial role in enhancing the cell cycle progression of anti-CD3-activated CD8^(+)T cells in vitro and the anti-apoptotic effects of 4-1BB signaling on these cells.

关键词： AMPK CD8^(+)T cells 4-1BB(CD137) LKB1 metabolism

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4-1BB-4-1BBL cis-interaction contributes to the survival of selfreactive CD8^(+)T cell

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Cellular & Molecular Immunology 2023年第9期20卷 1077-1080页

作者： Eunjung Cho Rohit Singh chungyong han Seon-Hee Kim Kwang H.Kim Bo-Mi Park Dong Hoon Shin Seongeun han Young H.Kim Byoung S.Kwon Ki Taek Nam Beom K.Choi Immuno-oncology Branch Division of Rare and Refractory CancerNational Cancer CenterGoyang 10408Republic of Korea Severance Biomedical Science Institute Brain Korea 21 Project for Medical ScienceYonsei University College of MedicineSeoulRepublic of Korea Department of Cancer Biomedical Science Graduate School of Cancer Science and PolicyNational Cancer CenterGoyang 10408Republic of Korea Department of Biomedical Laboratory Science Catholic Kwandong UniversityGangneung 25601Republic of Korea Biomedicine Production Branch Research InstituteNational Cancer CenterGoyang 10408Republic of Korea Anticancer Resistance Branch Division of Rare and Refractory CancerResearch InstituteNational Cancer CenterGoyang 10408Republic of Korea Eutilex Co. Ltd.Geumcheon-guSeoul 08594Republic of Korea Department of Medicine Tulane University Health Sciences CenterNew OrleansLA 70112USA Innobationbio Co. Ltd.Mapo-guSeoul 03929Republic of Korea

4-1BB is an inducible receptor expressed on activated T cells,while its ligand,4-1BBL,is mainly expressed in antigen-presenting cells and macrophages[1,2].To the best of our knowledge,ligandmediated transactivation of... 详细信息

关键词： interaction activation knowledge

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Chronic activation of 4-1BB signaling induces granuloma development in tumor-draining lymph nodes that is detrimental to subsequent CD8^(+)T cell responses

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Cellular & Molecular Immunology 2021年第8期18卷 1956-1968页

作者： Seon-Hee Kim Rohit Singh chungyong han Eunjung Cho Yu I.Kim Don G.Lee Young H.Kim Sang Soo Kim Dong Hoon Shin Hye Jin You Hyeon-Woo Lee Byoung S.Kwon Beom K.Choi Division of Tumor Immunology National Cancer CenterGoyang10408Republic of Korea Graduate School of Cancer Science and Policy National Cancer CenterGoyang10408Republic of Korea Biomedicine Production Branch Program for Immunotherapy ResearchGoyang10408Republic of Korea Eutilex Institute for Biomedical Research EutilexCo.Ltd.Seoul08594Republic of Korea Division of Convergence Technology National Cancer CenterGoyang10408Republic of Korea Division of Translational Science National Cancer CenterGoyang10408Republic of Korea Institute of Oral Biology School of DentistryGraduate SchoolKyung Hee UniversitySeoul02447Republic of Korea Department of Medicine Tulane University Health Sciences CenterNew OrleansLA70112USA

The antitumor capabilities of agonistic anti-4-1BB mAbs have made them an attractive target for tumor ***,the adverse side effects associated with agonist antibodies have hindered their clinical ***,we aimed to study the immune-related adverse events of repeated doses and long-term use of agonistic anti-4-1BB *** show that chronic activation of 4-1BB signals induced the accumulation of IFN-γ-producing PD-1^(+)CD8^(+)T cells in the secondary lymphoid organs of tumor-bearing mice by increasing the number of dividing CD8^(+)T cells,which was beneficial for suppressing tumor growth in the early phase of anti-4-1BB ***,repeated exposure to anti-4-1BB mAbs led to granuloma development in tumor-draining lymph nodes(TDLNs)of mice due to recruitment and accumulation of macrophages via the CD8^(+)T cell-IFN-γ*** was accompanied by excessive lymph node swelling,which impaired the sequential activation of CD8^(+)T *** data provide insights into the immune-related adverse events of long-term agonist 4-1BB antibody dosing,which should be considered during the clinical development of immunomodulating therapy.

关键词： 4-1BB Costimulation Granuloma CD8 lymphocyte Macrophage

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