Lymphangiogenesis-inducing vaccines elicit potent and long-lasting T cell immunity against melanomas

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.