Improving T-Cell Activation and Serial Killing Through Metabolic Modulation

Article Improving T-Cell Activation and Serial Killing Through Metabolic Modulation Introduction T cells are an essential part of the anti-cancer immune response, particularly cytotoxic CD8+ T cells, which can recognize and destroy malignant cells. Harnessing the killing potential of T cells through immunotherapy has revolutionized cancer treatment and significantly improved patient survival outcomes.1 T cell-based immunotherapies take several different forms, including checkpoint inhibitors .1 (which block the binding of inhibitory proteins to T cell inhibitory receptors) and chimeric antigen receptor (CAR)-T cells (in which cells are engineered to express synthetic antigen receptors that direct and enhance cancer cell targeting). Despite the successes of T cell immunotherapies, the tumor microenvironment (TME) poses a key barrier to efficient anti-tumor responses, limiting the success of CAR T cells against solid tumors. T cell metabolic fitness is essential to meet the demands of mounting an appropriate immune response, and to ensure survival, expansion and differentiation. While strong stimulation can promote fitness by enhancing survival and effector functions, over-stimulation can result in an exhausted, non-functional phenotype. The TME is highly hostile to immune cells and creates a nutrient-deficient environment that inhibits the metabolism, and therefore functions, of T cell-based immunotherapies.2 Subsequently, T cells – and T cell-based immunotherapies – become exhausted, .2 showing overexpression of inhibitory receptors, metabolic dysfunction, decreased cytokine production and reduced cytolytic activity. 3 Recent research has shown that the inhibitory effects of the TME on immunotherapy effectiveness could be counteracted by engineering T cell metabolism to improve persistence and fitness. Strategies include adjusting cytokine profiles during manufacture and manipulation of T-cell differentiation to improve persistence in CAR T cells Combination of checkpoint therapies with .4,5 other synergistic metabolic drugs, or with other immunotherapies such as CAR T cells or cancer vaccines, is also being attempted. 6 If the efficacy of immunotherapies is to be improved through metabolic modulation, then highly accurate measuring of T cell metabolism and persistence is of the utmost importance. This editorial will discuss how T cell metabolism is being evaluated and manipulated for the improvement of T cell based immunotherapies, and the platforms — both established and novel — involved in advancing this field.