Abstract ES6-1: How tumor metabolism contributes to the immunosuppressive microenvironment

Abstract

Abstract Lymphocyte activation leads to rapid proliferation and differentiation and we have shown that T cell subsets require distinct metabolic programs. The effector CD4 T cell fates (Th1, Th2, Th17) activate a highly glycolytic program. Regulatory CD4 T cells (Treg), in contrast, utilize a more oxidative metabolism and utilize lipids as a major fuel. These metabolic distinctions may allow new understanding of T cell function in tumors and approaches to manipulate immunity. We have now examined the metabolism of Treg in detail and found that FoxP3 itself can promote oxidative metabolism characteristic of Treg and that this is critical to maximize Treg suppressive capacity. Treg can be glycolytic and proliferative in vivo. We found, however, that glucose uptake and glycolysis impaired Treg stability. Thus, Treg regulate glycolytic and oxidative metabolism to balance proliferation and suppressive function. Conversely, the requirement of effector T cells for glucose uptake and glycolysis poses a barrier to inflammatory function in tumors. We have analyzed the metabolism of CD8 T cells in clear cell Renal Cell Carcinoma (ccRCC) and identified multiple metabolic defects. Importantly, bypassing these defects can enhance T cell function, demonstrating that metabolic alterations pose barriers to anti-tumor immunity. Understanding mechanisms that regulate T cell metabolism may provide new tools to modulate immunity the balance of T cell effector and regulatory populations. Citation Format: Rathmell JC. How tumor metabolism contributes to the immunosuppressive microenvironment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES6-1.