Journal Article

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

Young, Kirsten, Barone, Sierra, Smith, Christof C., Irish, Jonathan M., Siska, Peter J., Healey, Diana C. Contreras, Rathmell, Jeffrey C., Hongo, Rachel, Carbonell, Katie, Roe, Caroline E., Vincent, Benjamin G., Mason, Frank M., Beckermann, Kathryn E., Ye, Xiang, Rathmell, W. Kimryn

2020

Overview

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.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Carcinoma, Renal Cell - metabolism / Carcinoma, Renal Cell - pathology / CD28 antigen / CD28 Antigens - metabolism / CD8 antigen / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - metabolism / CD8-Positive T-Lymphocytes - pathology / Cell activation / CTLA-4 protein / Cytochrome / Deoxyglucose / Gene expression / Gene Expression Regulation / Genotype & phenotype / Glucose / Glucose - metabolism / Glycolysis / Humans / Immunology / Immunotherapy / Interleukin-7 - pharmacology / Kidney cancer / Kidney Neoplasms - metabolism / Kidney Neoplasms - pathology / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - drug effects / Lymphocytes, Tumor-Infiltrating - metabolism / Lymphocytes, Tumor-Infiltrating - pathology / Membrane potential / Metabolic pathways / Metabolic rate / Metabolism / Mitochondria / Mitochondria - metabolism / Nephritis - metabolism / Nephritis - pathology / Oncology / Oxidative metabolism / Patients / PD-1 protein / Phenotypes / Phosphorylation / Renal cell carcinoma / Renal function / Single-Cell Analysis / T cell receptors / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumor-infiltrating lymphocytes / Tumors