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CD28 costimulation drives tumor-infiltrating T cell glycolysis to promote inflammation.
Beckermann, Kathryn E; Hongo, Rachel; Ye, Xiang; Young, Kirsten; Carbonell, Katie; Healey, Diana C Contreras; Siska, Peter J; Barone, Sierra; Roe, Caroline E; Smith, Christof C; Vincent, Benjamin G; Mason, Frank M; Irish, Jonathan M; Rathmell, W Kimryn; Rathmell, Jeffrey C.
Afiliação
  • Beckermann KE; Department of Medicine, Division of Hematology and Oncology, and.
  • Hongo R; Department of Medicine, Division of Hematology and Oncology, and.
  • Ye X; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Young K; Department of Medicine, Division of Hematology and Oncology, and.
  • Carbonell K; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Healey DCC; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Siska PJ; Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
  • Barone S; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
  • Roe CE; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
  • Smith CC; Lineberger Comprehensive Cancer Center; Department of Medicine Division of Hematology and Oncology, Department of Microbiology and Immunology, Curriculum in Bioinformatics and Computational Biology, Computational Medicine Program, University of North Carolina (UNC), Chapel Hill, North Carolina, USA.
  • Vincent BG; Lineberger Comprehensive Cancer Center; Department of Medicine Division of Hematology and Oncology, Department of Microbiology and Immunology, Curriculum in Bioinformatics and Computational Biology, Computational Medicine Program, University of North Carolina (UNC), Chapel Hill, North Carolina, USA.
  • Mason FM; Department of Medicine, Division of Hematology and Oncology, and.
  • Irish JM; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
  • Rathmell WK; Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Rathmell JC; Department of Medicine, Division of Hematology and Oncology, and.
JCI Insight ; 5(16)2020 08 20.
Article em En | MEDLINE | ID: mdl-32814710
Metabolic reprogramming dictates the fate and function of stimulated T cells, yet these pathways can be suppressed in T cells in tumor microenvironments. We previously showed that glycolytic and mitochondrial adaptations directly contribute to reducing the effector function of renal cell carcinoma (RCC) CD8+ tumor-infiltrating lymphocytes (TILs). Here we define the role of these metabolic pathways in the activation and effector functions of CD8+ RCC TILs. CD28 costimulation plays a key role in augmenting T cell activation and metabolism, and is antagonized by the inhibitory and checkpoint immunotherapy receptors CTLA4 and PD-1. While RCC CD8+ TILs were activated at a low level when stimulated through the T cell receptor alone, addition of CD28 costimulation greatly enhanced activation, function, and proliferation. CD28 costimulation reprogrammed RCC CD8+ TIL metabolism with increased glycolysis and mitochondrial oxidative metabolism, possibly through upregulation of GLUT3. Mitochondria also fused to a greater degree, with higher membrane potential and overall mass. These phenotypes were dependent on glucose metabolism, as the glycolytic inhibitor 2-deoxyglucose both prevented changes to mitochondria and suppressed RCC CD8+ TIL activation and function. These data show that CD28 costimulation can restore RCC CD8+ TIL metabolism and function through rescue of T cell glycolysis that supports mitochondrial mass and activity.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma de Células Renais / Linfócitos do Interstício Tumoral / Antígenos CD28 / Neoplasias Renais / Nefrite Limite: Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma de Células Renais / Linfócitos do Interstício Tumoral / Antígenos CD28 / Neoplasias Renais / Nefrite Limite: Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article