If detected early melanoma is usually curable with surgery, however, melanomas are often detected at later stages after cancer cells have metastasized when survival rates are less than 15%. Furthermore, some thin melanomas, even when detected early, lead to mortality. What defines this difference in outcome is largely unknown and suggests a need for new markers that can predict a patient’s risk. New immune-based therapies are extremely effective but still do not work for all patients and response is predicted by presence of an active immune response within the tumor microenvironment. Why some patients lack an active immune response and thereby do not respond to therapy, however, remains largely unknown. Lymphatic vessels are required for the generation of immune responses and in melanoma correlate with poor outcome, yet we do not understand the contribution of lymphatic vessels to active immune responses in cancer. In this proposal we will investigate the role of lymphatic vessels in setting up active immunity in melanoma using both mouse and human data. We will perform an analysis of archived melanoma tissues to determine the relationship between lymphatic vessels and immunity in human melanoma and we will use a mouse model to track immune responses over time and determine how lymphatic vessels might contribute to their suppression. We hypothesize that lymphatic vessels regulate local immune responses and are therefore a biomarker that may predict response to therapy. Understanding the underlying biology that regulates immune responses in human melanoma will allow better patient risk stratification and prognosis. Stratification of patients based upon their unique immune profiles, including lymphatic vessels, will guide rational, personalized administration of combination therapy for optimal clinical benefit, to provide long-lasting, durable responses for patients with metastatic