Abstract B93: Tumor lymphangiogenesis improves responsiveness to radiotherapy in mouse melanoma

Abstract

Abstract Radiotherapy (RT) constitutes a significant component of clinically used cancer therapy, with approximately 50% of all cancer patients receiving treatment over the course of their disease. RT is known to induce immunogenic cell death of tumor cells, leading to the release of tumor antigens, damage-associated molecular patterns, and other tumor-resident components such as cytokines. This phenomenon drives the initiation of antigen-specific immune responses, which have been shown to be essential for the complete response to RT. Notwithstanding its broad applicability and diverse mechanisms of action, RT does not usually lead to curative responses and combinations with other treatment modalities are needed to improve efficacy. Our laboratory and others have previously demonstrated that tumor-associated lymphatics can actively influence antitumor immune responses and potentiate immunotherapy. Here, we investigate whether lymphangiogenesis influences the antitumor efficacy and immune response elicited by RT. We employed the aggressive B16F10 melanoma model, that was either transduced to overexpress the lymphangiogenic factor VEGF-C (B16-VEGF-C) or mock-transduced (B16-ctrl). Tumor-bearing animals were treated by ablative localized RT and monitored for tumor growth and survival, while antitumor immune responses were assessed by flow cytometry and ELISA. We found that the therapeutic response to RT was stronger in B16-VEGF-C melanomas compared to B16-ctrl, as evidenced by a significant delay in tumor growth and prolonged animal survival. In agreement with this finding, B16-VEGF-C melanomas exhibited a significantly greater CD8+ T-cell infiltration and activation upon ex vivo restimulation after RT. These responses were partially inhibited by a function-blocking antibody of the main VEGF-C receptor, VEGFR3. Together, our findings demonstrate that lymhangiogenesis may be a key contributing factor underlying tumor responsiveness to RT. Citation Format: Nikolaos Mitrousis, Maria Stella Sasso, Ralph R. Weichselbaum, Jeffrey A. Hubbell, Melody A. Swartz. Tumor lymphangiogenesis improves responsiveness to radiotherapy in mouse melanoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B93.