Project Summary In melanoma and other cancers, the expansion of the local lymphatic network via expression of VEGF-C in the tumor microenvironment promotes metastasis and is widely correlated with poor prognosis. We and others have shown that VEGF-C-activated lymphatic vessels play important immune suppressive roles in the tumor microenvironment. Paradoxically, we have observed that in mouse melanoma models, lymphangiogenic tu- mors were more responsive to immunotherapy, including in adoptive T cell therapy, dendritic cell vaccines, and protein vaccination. Here we propose a research program that explores this other side of tumor lymphangio- genesis, and suggest a novel hypothesis that while VEGF-C in the tumor microenvironment can induce in- flammation and immune suppression, it also enhances the infiltration of naïve T cell infiltration, at least in part by upregulating the lymphoid homing chemokine CCL21. This enhanced infiltration, in turn, can prime the tu- mor for enhanced responsiveness to immunotherapy. Three aims are proposed to explore (i) validation and mechanistic underpinnings in mouse models, (ii) relevance to human melanoma, and (iii) translational applica- tion.