Targeting Glycerol Metabolism in anti-Tumor Immunity

Dr. Yao’s laboratory studies metabolic regulation in cancer with a special interest in how obesity correlates with increased cancer incidence and mortality. Much of the study on the effect of a high fat state on cancer has focused on the three molecules of fatty acids that make up molecule of triglyceride, but how the glycerol backbone in triglycerides contributes to tumorigenesis and anti-tumor immunity remains largely unexplored. Dr. Yao is particularly interested in CD8+ T cells; CD8+T cells are key anti-tumor effector cells that 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, especially in the context of a high-fat state, remains largely unknown. Dr. Yao has found that glycerol supplementation alone is sufficient to accelerate tumor growth in a CD8+ T cell dependent manner. Thus, she hypothesizes that glycerol, as a potential immunosuppressive metabolite, is secreted by cancer cells and catabolized by cells to impair their anti-tumor function.

To test this hypothesis and figure out the underlying mechanism, Dr. Yao will study the immunomodulatory role of glycerol metabolism in tumor-immune crosstalk, focusing on the possibility that increased glycerol availability due to neighboring cancer cell secretion or glycerol supplementation impairs T cell metabolism and anti-tumor functions and leads to T cell exhaustion. Further, to test whether blocking glycerol will improve anti-tumor immunity, she will employ both in vitro and animal studies to see if limiting glycerol secretion slows tumor growth. If her hypothesis proves correct, these studies will provide new targets and ways to use T cells to both treat and possibly prevent cancer, particularly in overweight and obese patients.