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

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

doi:10.1172/jci.insight.138729

Abstract

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.

Highlights

Glucose is a fundamental anabolic nutrient for proliferating cells [1]
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)
To investigate pathways regulating T cell function and metabolism in the RCC tumor microenvironment, CD8+ T cells were sorted from the tumors of 5 patients with RCC, and gene expression was compared with that in matched patient peripheral blood CD8+ T cells

Summary

Introduction

Glucose is a fundamental anabolic nutrient for proliferating cells [1]. It is clear that stimulated T cells are highly dependent on metabolic reprogramming from a catabolic oxidative metabolism to an anabolic metabolism with elevated glucose consumption and aerobic glycolysis to develop effector function [2,3,4]. T cell activation leads to increased Myc and PI3K/Akt/mTORC1 signaling activity to promote glucose uptake and mitochondrial metabolism for growth, energetics, and to regulate signaling and gene expression pathways [5,6,7,8]. These changes are critical for effector T cell function, as T cells deficient in the glucose transporter GLUT1 or subject to inhibition of glucose metabolism fail to develop into effector subsets, have reduced capacity to induce inflammatory diseases, and instead favor suppressive Treg fates [9].

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Results

Conclusion