METABOLIC MODULATION OF CANCER AND THE IMMUNE RESPONSE

Abstract

Metabolism is a central aspect of life, encompassing all biochemical transformations required for growth, reproduction, and homeostasis. These include nutrient uptake, chemical conversion of substrates and energy, and excretion of cellular waste. Tissues that rapidly divide, like active lymphocytes and tumors, are metabolically wired to transform available nutrients into the biosynthetic precursors needed to meet their proliferative agendas. Accordingly, perturbation of these processes can impact the immune response or impair cancer cell growth.

Here, we investigate the metabolic demands for lymphocyte function and cancer using three approaches for modulating metabolism. First, we explore how T cells rely on their nutrient environment. We discover that T cells require exogenous alanine to undergo a normal activation program, and that this alanine is primarily used for protein synthesis. Moreover, limiting access to extracellular alanine impairs T cell function. Next, we shift our focus to how proliferating cells endogenously produce the high-energy intermediate nicotinamide adenine dinucleotide phosphate (NADPH), a critical substrate for reductive biosynthesis and redox homeostasis. We explore the role of G6PD, a key enzyme for producing NADPH via the oxidative pentose phosphate pathway (oxPPP). We develop LC-MS based target engagement assays to monitor G6PD activity in cells, and use these to develop small molecule tool compounds that demonstrate cellular G6PD inhibition. Employing these tools leads to the discovery that lymphocytes depend on oxPPP activity for maintaining cellular NADPH and for producing cytokines, while sparing other aspects of lymphocyte biology. Finally, we examine the role of G6PD in tumors. Previously work has shown that cancer cells in culture cope with G6PD loss through compensatory NADPH production, but it was unclear whether this could occur in vivo. Using a battery of modern genetic techniques, we knocked out G6PD in various murine tumor models. These studies show that G6PD provides some advantage to cells migrating through the blood, but is otherwise dispensable for solid tumor growth and metastasis.

In summary, this work provides novel tools and insights into the different metabolic demands of tumors and the immune response, and establishes a foundation for future studies exploring these areas of metabolism.