Abstract
In melanoma, the induction of lymphatic growth (lymphangiogenesis) has long been correlated with metastasis and poor prognosis, but we recently showed it can synergistically enhance cancer immunotherapy and boost T cell immunity. Here, we develop a translational approach for exploiting this "lymphangiogenic potentiation" of immunotherapy in a cancer vaccine using lethally irradiated tumor cells overexpressing vascular endothelial growth factor C (VEGF-C) and topical adjuvants. Our "VEGFC vax" induced extensive local lymphangiogenesis and promoted stronger T cell activation in both the intradermal vaccine site and draining lymph nodes, resulting in higher frequencies of antigen-specific T cells present systemically than control vaccines. In mouse melanoma models, VEGFC vax elicited potent tumor-specific T cell immunity and provided effective tumor control and long-term immunological memory. Together, these data introduce the potential of lymphangiogenesis induction as a novel immunotherapeutic strategy to consider in cancer vaccine design.