Abstract 1448: Lymphangiogenesis-inducing whole-cell vaccine against melanoma promotes broad tumor-specific T cell immunity and effective tumor control

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Abstract We recently reported that the growth of lymphatic vessels (lymphangiogenesis) in mouse melanomas dramatically enhances the efficacy of immunotherapy by promoting immune cell infiltration and broadening the anti-tumor T cell repertoire (Fankhauser et al, Sci. Trans. Med. 2017). Correlative evidence supporting such ‘lymphangiogenic potentiation’ was also seen in human melanoma patients, suggesting a possible immunotherapeutic use of the pro-lymphangiogenic growth factor VEGFC. On the other hand, tumor lymphangiogenesis is known to promote cancer cell dissemination and metastasis, raising concerns about the possibility of manipulating lymphatic vessels directly within the tumor site as a treatment strategy for cancer immunotherapy. Here, we sought to manipulate and 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 vaccines were formulated using lethally irradiated B16F10 or B16F10-OVA mouse melanoma cells, either mock-transduced or genetically modified to overexpress VEGFC, and combined with topically retained immune adjuvants (ctrl-vax and VEGFC-vax, respectively). Upon intradermal injection, VEGFC-vax induced extensive local lymphatic growth and stimulated increased lymphatic transport from the vaccine site to the draining lymph nodes. Consistently with our previous study, VEGFC induced CCL21 upregulation and local recruitment of CCR7+ naïve T cells, which could undergo in situ priming in the vaccine site. Compared to ctrl-vax, VEGFC-vax elicited a robust T cell response directed against multiple mouse melanoma antigens, as assessed by ex vivo antigen stimulation and IFNγ ELISPOT. In a prophylactic vaccine setting, VEGFC-vax induced stronger tumor-specific T cell immunity and greater protection from tumor challenge compared to both ctrl-vax as well as a GM-CSF-secreting whole-cell vaccine. Overall this study provides a proof of concept for the use of VEGFC in cancer vaccines and characterizes a whole-cell lymphangiogenesis-inducing vaccine formulation with potential for clinical translation. Citation Format: Maria Stella Sasso, Sylvie Hauert, Priscilla S. Briquez, Yue Wang, Jun Ishihara, Jeffrey A. Hubbell, Melody A. Swartz. Lymphangiogenesis-inducing whole-cell vaccine against melanoma promotes broad tumor-specific T cell immunity and effective tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1448.