Project Summary – Project 1 Our previous data have shown that the aged microenvironment drives resistance to targeted therapy, and may impact response to immunotherapy as well. Tumor cells undergo metabolic reprogramming in order to acquire resistance to BRAF/MEK inhibitors. We have found that one of the contributing factors to this resistance may be lipids. Aged or stressed fibroblasts secrete lipids, which are taken up by melanoma cells, promoting their ability to invade, and resist targeted therapy. These stromally-induced changes can also affect immune cells. Dendritic cells (DC) are required for the initiation and maintenance of immune responses and lipid accumulation in DC decreases their ability to act as antigen presenting cells. Myeloid derived suppressor cells (MDSCs) play a major role in regulation of antitumor immunity. These cells thrive on lipid metabolism and they accumulate and use oxidized lipids to augment their ability to suppress the immune microenvironment. We have implicated fatty acid (FA) transporter protein 2 (FATP2) in lipid accumulation by both tumor cells and PMN-MDSC, suggesting a complex crosstalk between multiple components of the TME. We propose to identify the mechanism and subsequent functional consequences of lipid accumulation in tumor cells and MDSCs. We will evaluate the effect of therapeutic targeting of lipid accumulation in MDSCs on the generation of immune responses in melanoma models, and on tumor cell fate and response to targeted therapy.