Targeting Glycerol Metabolism in anti-Tumor Immunity - Project Summary. Research. Obesity contributes to increased cancer incidence and mortality, yet the mechanisms involved and impact on therapy remain unclear. Since greater than 50% of adults in the United States are obese, elucidating the mechanistic consequences of high-fat state on cancer is critical to prevent an emerging health epidemic. One molecule of fat, or triglyceride, consists of three molecules of fatty acids and one molecule of glycerol. However, the majority of cancer research focuses on fatty acid metabolism of fats whereas the contribution of glycerol backbone to tumorigenesis and anti-tumor immunity remains largely unexplored. CD8+ T cells are key anti-tumor effector cells as they acquire cytotoxic activity and can directly kill tumor cells. Metabolic pathways are crucial for T cell activation and differentiation, but the mechanisms by which cancer cells compromise the metabolic fitness of CD8+ T cells in the tumor microenvironment, especially in the context of high-fat state, remain largely unknown. Based on my postdoctoral work, I discovered a novel paradigm of tumor-immune interaction mediated by glycerol. I found that glycerol supplementation alone was sufficient to accelerate tumor growth in a CD8+ T cell dependent manner. Thus, I hypothesize that glycerol, as a potential immunosuppressive metabolite, is secreted by cancer cells and catabolized by T cells to impair their anti-tumor functions. To test this hypothesis, Aim 1 will determine the immunomodulatory roles of glycerol on CD8+ T cells and then mechanistically study the metabolic interactions between cancer cells and T cells by using innovative coculture system and spatial mass spectrometry. Lastly, I will improve anti-tumor immunity by manipulating glycerol crosstalk. Aim 2 will define how dietary glycerol remodels the tumor microenvironment and determine cellular and molecular mechanisms by which excessive glycerol reshapes immune landscape and impairs anti-tumor immunity. Candidate. Dr. Conghui Yao, is the PI for this research proposal. She has worked as a postdoctoral fellow for the past four years at Harvard Medical School studying the metabolic regulations for CD8+ T cell activation and anti-tumor functions. She has accepted the tenure-track faculty offer from University of Chicago and will start her own lab this fall. Conghui has mapped out a detailed professional development plan enabling her to transition to an independent research career where she will develop her research program on tumorigenesis and anti-tumor immunity. She aims to become a leader in cancer immunology by applying an innovative systems biology approach and in vivo spatial metabolomics to dissect the tumor-immune crosstalk, which will distinguish her independent work from that of her postdoctoral mentors. Her long-term goal is to lead an independent cancer research program dedicated to the discovery of molecular mechanisms within tumors that regulate local immune responses and tumor progression. Conghui’s work will inform strategies and identify novel therapeutic targets for improving cancer immunotherapy outcomes especially relevant to overweight and obese patients.
