Starved and Asphyxiated: How Can CD8(+) T Cells within a Tumor Microenvironment Prevent Tumor Progression.

Ying Zhang,Hildegund C J Ertl

doi:10.3389/fimmu.2016.00032

Abstract

Although cancer immunotherapy has achieved significant breakthroughs in recent years, its overall efficacy remains limited in the majority of patients. One major barrier is exhaustion of tumor antigen-specific CD8+ tumor-infiltrating lymphocytes (TILs), which conventionally has been attributed to persistent stimulation with antigen within the tumor microenvironment (TME). A series of recent studies have highlighted that the TME poses significant metabolic challenges to TILs, which may contribute to their functional exhaustion. Hypoxia increases the expression of coinhibitors on activated CD8+ T cells, which in general reduces the T cells’ effector functions. It also impairs the cells’ ability to gain energy through oxidative phosphorylation. Glucose limitation increases the expression of programed cell death protein-1 and reduces functions of activated CD8+ T cells. A combination of hypoxia and hypoglycemia, as is common in solid tumors, places CD8+ TILs at dual metabolic jeopardy by affecting both major pathways of energy production. Recently, a number of studies addressed the effects of metabolic stress on modulating CD8+ T cell metabolism, differentiation, and functions. Here, we discuss recent findings on how different types of metabolic stress within the TME shape the tumor-killing capacity of CD8+ T cells. We propose that manipulating the metabolism of TILs to more efficiently utilize nutrients, especially during intermittent periods of hypoxia could maximize their performance, prolong their survival and improve the efficacy of active cancer immunotherapy.

Highlights

Following antigenic stimulation, differentiation of naive CD8+ T cells into effector cells is accompanied by metabolic reprograming to accommodate their increased demand for energy and biomass formation
Once T cells are past the acute activation phase, they resume energy production through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), which is partially supported by fatty acid oxidation (FAO) [7, 8]
We propose that CD8+ T cell exhaustion may be triggered by metabolic stress within the tumor microenvironment (TME)

Summary

INTRODUCTION

Differentiation of naive CD8+ T cells into effector cells is accompanied by metabolic reprograming to accommodate their increased demand for energy and biomass formation. Once T cells are past the acute activation phase, they resume energy production through the TCA cycle and OXPHOS, which is partially supported by fatty acid oxidation (FAO) [7, 8] One facilitator of this metabolic switch is increased expression of PD-1, a coinhibitor that blocks CD28-mediated activation of the mTOR pathway [9] and reduces glycolysis and promotes lipid metabolism [10]. Hypoxia may increase the suppressive activity of tumor-infiltrating myeloid suppressor cells and tumor-associated macrophages, which will lead to further impairments of CD8+ TIL functions [37, 38] Overall, all of these studies strongly suggest that lack of O2 negatively affects metabolism and functions of CD8+ TILs. reduces the T cells’ energy expenditure by blocking production of cytokines [49]. This in turn invites the testing of metabolic drugs that reprogram T cell metabolism as adjuvant treatments for active cancer immunotherapy or adoptively transferred TA-specific T cells

METABOLISM AND FUNCTIONS OF TILs

FUNCTIONS AND METABOLISM

CONCLUSION