Metabolic Consequences of T-cell Costimulation in Anticancer Immunity.

ABSTRACT

T-cell functional behavior and performance are closely regulated by nutrient availability and the control of metabolism within the T cell. T cells have distinct energetic and anabolic needs when nascently activated, actively proliferating, in naïveté, or in a resting, memory state. As a consequence, bioenergetics are key for T cells to mount adequate immune responses in health and disease. Solid tumors are particularly hostile metabolic environments, characterized by low glucose concentration, hypoxia, and low pH. These metabolic conditions in the tumor are known to hinder antitumor immune responses of T cells by limiting nutrient availability and energetic efficiency. In such immunosuppressive environments, artificial modulation of glycolysis, mitochondrial respiratory capabilities, and fatty acid ß-oxidation are known to enhance antitumor performance. Reportedly, costimulatory molecules, such as CD28 and CD137, are important regulators of metabolic routes in T cells. In this sense, different costimulatory signals and cytokines induce diverse metabolic changes that critically involve mitochondrial mass and function. For instance, the efficacy of chimeric antigen receptors (CAR) encompassing costimulatory domains, agonist antibodies to costimulatory receptors, and checkpoint inhibitors depends on the associated metabolic events in immune cells. Here, we review the metabolic changes that costimulatory receptors can promote in T cells and the potential consequences for cancer immunotherapy. Our focus is mostly on discoveries regarding the physiology and pharmacology of IL15, CD28, PD-1, and CD137 (4-1BB).