Emerging concepts of T cell metabolism as a target of immunotherapy

Abstract

T cells have a pivotal protective role in defense against infection and cancer but also are instrumental in the development of many autoimmune diseases. 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 alter their function and longevity. While the importance of T cell metabolic remodeling in different physiological settings is not fully understood, there is a growing realization that inappropriate metabolic remodeling underlies many aberrant immune responses and that manipulating cellular metabolism can beneficially enhance or temper immunity. Here we comment on the basic metabolic pathways in T cells, followed by a discussion on up-to-date findings about the relationship between metabolism and T cell function and longevity. Furthermore, we expand on potential approaches and applications in which T cells might be manipulated by the reprogramming of metabolic pathways for therapeutic purposes.

Figure 1. Basic metabolic pathways in a T cell

Glucose, glutamine, and fatty acids are main nutrients that support T cell bioenergetics and biosynthesis. Cells use nutrients to generate ATP via glycolysis (in the cytosol) or via oxidative phosphorylation (in the mitochondria). The intermediates generated in the glycolysis pathway and the tricarboxylic acid (TCA) cycle also serve as substrates for biosynthesis. FAO (fatty acid oxidation); FAS (fatty acid synthesis); PPP (pentose phosphate pathway).

Figure 2. Metabolic interplay in the local microenvironment

Competition for nutrients and metabolites, as well as other factors, between immune cells and other cells in a microenvironment can mediate T cell differentiation and function. Blockade antibodies may also influence cellular metabolism and thus change the availability of local substrates. The balance of these factors may affect T cell function, hence altering the fate of the immune response and disease development.

Figure 3. Targeting T cell metabolism for therapy

The schematic shows potential strategies to design more effective therapies against cancer by altering cellular metabolism. T cells could be metabolically modulated in vitro to promote mitochondrial integrity and oxidative metabolism, which will better support their function and longevity. T cell efficacy could be enhanced in vivo by taking steps to ensure that anti-tumor T cells enter a more nutrient replete environment.