Project Summary: Metabolic transformation is a hallmark feature of cancer cells that allows sustained anabolic metabolism to fuel cell growth and proliferation, and when distilled to its core, cancer is ultimately a disease of unchecked anabolic metabolism. Yet, it is not well understood how the aberrant metabolic activity of tumor cells affects the function, phenotype and metabolic states of neighboring immune cells in the tumor microenvironment. The development of new immunotherapies that stimulate anti-tumor T cell responses to control or eradicate cancer is a revolutionary and promising area of cancer therapy, but the immunosuppressive nature of the tumor microenvironment remains the biggest obstacle to increasing the frequency of patients that respond to immunotherapy. We propose that a major component dictating whether the tumor microenvironment (TME) is immuno-supportive or immuno-suppressive is the metabolic state of tumor cells. This model is based on the fact that, like tumor cells, tumor infiltrating lymphocytes (TILs) also require high rates of aerobic glycolysis and glutaminolysis to proliferate and perform tumoricidal effector functions. It is well documented that CD8+ T cells are functionally suppressed or “exhausted” in tumors and perhaps a primary source of this suppression is simply nutrient deprivation stemming from competition between metabolically active tumor and immune cells for the same nutrients. This model of a “metabolic tug-of-war” between tumor and immune cells over nutrients such as glucose and glutamine presents an entirely different perspective on how an immunosuppressive TME may form. To bridge this gap in cancer immunology, we will determine how metabolic pathways, particularly those involved in lipid homeostasis, utilized by melanoma and pancreatic ductal adenocarcinoma (PDAC) affect the quality and function of infiltrating immune cells. Specifically, in Aim 1 we will investigate the balance between lipogenesis and lipolysis in tumor cells to determine how this affects the composition of lipids and lipoproteins in the TME and the types of TILs present. We will test if CD8+ TILs metabolically adapt to changes in tumor cell metabolism and learn how this affects their anti-tumor immune response. In Aim 2, we will investigate if TILs respond to hyperlipidemia and Ox-LDL in the TME via upregulation of the transporter CD36 and elucidate how Ox-LDL-CD36 signaling suppresses CD8+ TIL effector functions (this work is the first to explore this pathway in CD8+ T cells to our knowledge). Lastly, we found arachidonic acid (AA) metabolism correlates with TIL infiltration and in Aim 3 we will explore a new model that the balance of PGD2 and PGE2 changes as tumors progress, converting an immuno-supportive TME to one that is more immuno-suppressive. In all three Aims we will target these metabolic pathways to discover novel combinations of therapies that enhance the efficacy of immunotherapies currently in clinical use today. ...