Tumor microenvironment metabolites directing T cell differentiation and function

Abstract

Metabolic reprogramming of cancer cells creates a unique tumor microenvironment (TME) characterized by the limited availability of nutrients, which subsequently affects the metabolism, differentiation, and function of tumor-infiltrating T lymphocytes (TILs). TILs can also be inhibited by tumor-derived metabolic waste products and low oxygen. Therefore, a thorough understanding of how such unique metabolites influence mammalian T cell differentiation and function can inform novel anticancer therapeutic approaches. Here, we highlight the importance of these metabolites in modulating various T cell subsets within the TME, dissecting how these changes might alter clinical outcomes. We explore potential TME metabolic determinants that might constitute candidate targets for cancer immunotherapies, ideally leading to future strategies for reprogramming tumor metabolism to potentiate anticancer T cell functions.

Keywords: T cells; metabolic reprogramming; metabolites; tumor immunotherapy; tumor microenvironment.

Figure 1.. Source and production of key metabolites.

Glucose is hydrolyzed via a series of enzymatic reactions to produce pyruvate, which then is imported into the mitochondria and consequently converted into acetyl-CoA to enter the TCA. Under anaerobic conditions, pyruvate is converted to lactate by LDH. Citrate is formed during TCA cycle. FAs are mainly derived from the hydrolysis of fats or synthesis from two carbon units (acetyl- or malonyl-CoA). FAs can also be up-taken from the extracellular microenvironment. Cholesterol is transported to the lysosomes through the endocytic pathway; it is then hydrolyzed to free cholesterol molecules. Cholesterol synthesis starts from the mevalonate pathway and is eventually yielded after multistep enzymatic reactions. MCT: monocarboxylate transporters; GLUT: glucose transporter; ATP: adenosine triphosphate; ADP: adenosine diphosphate; NAD⁺: nicotinamide adenine dinucleotide; NADH: nicotinamide adenine dinucleotide (NAD) + hydrogen (H); LDH: lactate dehydrogenase; PDC: pyruvate dehydrogenase complex; TCA: tricarboxylic acid cycle; FAs: Fatty acids. FABP: fatty acid-binding protein; FASN: fatty acid synthase; ACC: Acetyl CoA carboxylase; ACLY: ATP citrate lyase; LDL: low-density lipoprotein; HMGCR: 3-Hydroxy-3-Methylglutaryl-CoA Reductase

Figure 2.. Effects of key metabolites on effective anti-tumor immunity in the suppressive tumor microenvironment.

Tumor cells uptake large amounts of nutrients (glucose, glutamine, amino acids, etc.) from the TME for their energy demands, resulting in a nutrient-poor environment. Cancer cells have active aerobic glycolysis to produce lactic acid and contribute to an acidic environment. Accumulated lactic acid, fatty acid (FA), and cholesterol significantly suppress the proliferation, cytokine production, and cytotoxic activity of effector T cells; they also lead to the development of anergy or exhaustion in tumor-infiltrating CD8⁺ cells. Decreased amounts of some metabolites, such as citrate and PEP, also affect effector T cell functions in anti-tumor immunity. Tumor-infiltrating Tregs are activated and expanded in this specific TME, where they preferentially capture and utilize glucose to fuel glycolysis; meanwhile, they synthesize and accumulate FAs, which contribute to the suppression of antitumor immunity. In addition, tumor associated macrophages (TAM) exhibit increased FA synthesis, uptake, and oxidation. Myeloid derived suppressor cells (MDSC) also experience active glucose uptake, as well as the uptake of FA, glutamine, and acetate. PEP: phosphoenolpyruvate; Tregs: regulatory T cells;