Targeting T cell immunometabolism for cancer immunotherapy; understanding the impact of the tumor microenvironment

Abstract

The immune system has a key role to play in controlling cancer initiation and progression. T cell activation, which is central to anti-tumor immune responses, coincides with changes in cellular metabolism. Naïve T cells predominantly require an ATP generating metabolic profile, whereas proliferating effector T cells require anabolic metabolic profiles that promote rapid growth and proliferation. Furthermore, specific T cell subsets require distinct energetic and biosynthetic pathways to match their functional requirements. The often hostile tumor microenvironment can affect T cell immune responses by altering the resulting cellular metabolism. Tailoring immune responses by manipulating cellular metabolic pathways may provide an exciting new option for cancer immunotherapy. T cell responses might also be skewed via metabolic manipulation to treat the complications of obesity-associated inflammation, which is a rapidly growing global health problem and a major risk factor for many malignancies. In this review, the diverse metabolic requirements of T cells in anti-tumor immunity are discussed, as well as the profound influence of the tumor microenvironment and the possible avenues for manipulation to enhance anti-tumor immunity.

Keywords: T cells; cancer; immunometabolism; metabolic targeting agents; obesity.

Figure 1

Changes in T cell metabolism are related to function: Over the course of an immune response the metabolism of a T cell changes. Naïve T cells mainly used a mixed fuel OxPhos to produce ATP. Once activated the T cell adopts a metabolic profile that is similar to many cancer cells (Warburg effect). Consumption of glucose and glutamine increases to support increased cell growth and proliferation. A subset of activated T cells survives to become T_MEM reverting back to lipid oxidation with increased capacity for efficient energy generation and survival. Activation of T cells results in changes in migration patterns to ensure they can successfully migrate to areas of inflammation and cancer.

Figure 2

Activation of T cells results in metabolic reprograming, which influences their proliferation, differentiation, and effector functions. Aerobic glycolysis becomes the predominant metabolic pathway used by CD8⁺ effector cells, CD4⁺ Th1, Th2, and Th17 cells, by contrast T_REG and T_MEM rely on lipid oxidation. T cells that differentiate into Th17 cells primarily rely on glycolysis controlled by HIF-1α. T_MEM and T_REG rely on lipid oxidation under the control of AMPK. Tumor specific T_MEM cell prevalence can be enhanced through the inhibition of glycolysis following treatment with the hexokinase-2 inhibitor 2DG. In addition, inhibition of mTOR by rapamycin and activation of AMPK by the mitochondrial complex I inhibitor metformin can also led to increased survival of T_MEM cells. Etomoxir, a specific inhibitor of CPT1A results in the reduction of T_REG prevalence and has also shown promising results in delaying tumor development.