Impact of Metabolism on T-Cell Differentiation and Function and Cross Talk with Tumor Microenvironment

Abstract

The immune system and metabolism are highly integrated and multilevel interactions between metabolic system and T lymphocyte signaling and fate exist. Accumulating evidence indicates that the regulation of nutrient uptake and utilization in T cells is critically important for the control of their differentiation and manipulating metabolic pathways in these cells can shape their function and survival. This review will discuss some potential cell metabolism pathways involved in shaping T lymphocyte function and differentiation. It will also describe show subsets of T cells have specific metabolic requirements and signaling pathways that contribute to their respective function. Examples showing the apparent similarity between cancer cell metabolism and T cells during activation are illustrated and finally some mechanisms being used by tumor microenvironment to orchestrate T-cell metabolic dysregulation and the subsequent emergence of immune suppression are discussed. We believe that targeting T-cell metabolism may provide an additional opportunity to manipulate T-cell function in the development of novel therapeutics.

Keywords: T-lymphocytes; cancer; hypoxia; immune system; tumor cell metabolism; tumor microenvironment.

Figure 1

Metabolic reprogramming drives: (A) T-cell fate and function and (B) antitumor-immune response. (A) Upon activation through T-cell receptor (TCR) and costimulatory signals, T cells engage in growth, and differentiation into different cytotoxic, regulatory T cells (T_reg), helper T (Th), and memory T (T_m) subsets cells. Metabolic reprogramming has been shown to intimately support T-cell activation and differentiation. While naïve T cells rely on oxidative phosphorylation (OXPHOS) to maintain energy demand; activated T cells engage increased aerobic glycolysis and glutaminolysis consuming massive amount of glucose and glutamine, enabling to generate effector cytokines, including interferon-γ (IFN-γ) and IL-2. In contrast to cytotoxic and effector Th cells, the metabolic profile of T_reg and T_m cells rely on OXPHOS and fatty acid oxidation (FAO) to support their survival and differentiation. The central energy-monitoring system underlying this metabolic remodeling is the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway that boosts glycolytic activity in T cells via activation of transcription factors hypoxia-inducible factor-1α (HIF-1α) and Myc pathways. (B) Tumor-specific T cells are often rendered dysfunctional due to an immunosuppressive microenvironment. Infiltrating T cells are reprogrammed by the tumor favoring its survival and immune escape. Cancer cells induce several metabolic changes in the microenvironment. Tumor-mediated decreased extracellular nutrients levels cause impaired glycolysis capacity and IFN-γ production in T cells. Cancer cells also generate a hypoxic microenvironment. Hypoxia stabilizes HIF-1α and enhance glycolysis in tumor cells, a phenomenon recognized as “the Warburg effect.” HIF-1α also enhances constitutive expression of programmed death ligand-1 (PD-L1) leading to activation of Akt/mTOR pathway. Activating immune checkpoints and PD-L1 signaling through binding to its receptor programmed death-1 (PD-1) leads to dampening of the Akt-mTOR pathway and reduced T-cell glycolysis. Collectively, tumor environment affects metabolic fitness of infiltrating immune cells and drives impairment of antitumor effector function and increased tumor progression.