Lymphangiogenesis-Inducing Vaccines For Melanoma Treatment Elicit Potent Tumor-Specific T Cell Immunity And Long-Term Tumor Control

We recently demonstrated that the growth of tumor-associated lymphatic vessels (lymphangiogenesis) promotes immune infiltration in melanoma (Lund et al. 2016) and increases T cell activation following immunotherapy, resulting in strongly enhanced therapeutic efficacy (Fankhauser et a. 2017). On the other hand, tumor lymphangiogenesis is known to support cancer cell dissemination through the lymphatic route and metastasis formation. Therefore, inducing lymphangiogesis within the tumor site to boost anti-tumor immunity appears as a potentially unsafe therapeutic approach since it might also result in increased tumor metastatic potential. In this study, we sought to exploit the immune-promoting functions of lymphatics remotely from the tumor by developing a lymphangiogenesis-inducing cancer vaccine that mimics the microenvironment of a lymphangiogenic tumor. Whole-cell lymphangiogenic vaccines were generated using lethally irradiated mouse melanoma cells genetically engineered to overexpress the lymphatic-specific growth factor VEGFC, in combination with topical immune adjuvants (VEGFC vax). VEGFC vax was compared to control vaccines with identical formulation but lacking VEGFC overexpression and to a vaccine composed of GM-CSF-overexpressing tumor cells (GVAX), a vaccination approach that has been widely used in clinical studies. Upon intradermal injection in mice, VEGFC vax induced extensive lymphangiogenesis at the vaccine site and increased antigen transport to vaccine-draining lymph nodes. Analogously to what observed in lymphangiogenic tumors, we found that naive T cells significantly infiltrated lymphangiogenic vaccine sites and could undergo in situ priming and activation. Using VEGFC vaccines containing either B16-F10 mouse melanoma cells or melanoma cells obtained from tumors growing in BrafV600EPten−/- transgenic mice, we demonstrated that VEGFC vax elicits a potent tumor-specific T cell response. Importantly, VEGFC vaccination resulted in the mounting of a broad T cell immunity directed against multiple B16-F10-associated antigens. In both prophylactic and therapeutic settings, VEGFC vax provided effective tumor control and long-term protection against B16-F10 melanomas. In the present study we introduced for the first time the concept of lymphangenesis induction as a tool to increase cancer vaccine potency and we provided a proof of efficacy of lymphangiogenic vaccines in preclinical melanoma models. Citation Format: Maria Stella Sasso, Nikolaos Mitrousis, Sylvie Hauert, Priscilla S. Briquez, Yue Wang, Jun Ishihara, Jeffrey A. Hubbell, Melody A. Swartz. Lymphangiogenesis-inducing vaccines for melanoma treatment elicit potent tumor-specific T cell immunity and long-term tumor control [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1072.