CD28 costimulation drives tumor-infiltrating T cell glycolysis to promote inflammation.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Beckermann, KE; Hongo, R; Ye, X; Young, K; Carbonell, K; Healey, DCC; Siska, PJ; Barone, S; Roe, CE; Smith, CC; Vincent, BG; Mason, FM; Irish, JM; Rathmell, WK; Rathmell, JC

Published Date

  • August 20, 2020

Published In

Volume / Issue

  • 5 / 16

PubMed ID

  • 32814710

Pubmed Central ID

  • PMC7455120

Electronic International Standard Serial Number (EISSN)

  • 2379-3708

Digital Object Identifier (DOI)

  • 10.1172/jci.insight.138729

Language

  • eng

Conference Location

  • United States