Abstract 2253: Lymphangiogenesis augments the anti-tumor efficacy of radiotherapy in mouse melanoma

Abstract

Abstract Radiotherapy (RT) constitutes a significant component of cancer therapy in the clinic, with approximately 50% of all cancer patients receiving treatment over the course of their disease. In addition to acting as a DNA-damaging agent, RT leads to the release of tumor antigens, damage-associated molecular patterns, and cytokines, a process termed immunogenic cell death. This phenomenon triggers the initiation of anti-tumor immune responses, which have been shown to be essential for the complete therapeutic response to RT. Despite its diverse mechanisms of action and broad applicability, RT does not typically lead to curative responses and combinations with other treatment modalities such as immunotherapy are being explored to improve efficacy. Our laboratory and others have previously established that tumor-associated lymphatics can actively modulate anti-tumor immune responses and potentiate immunotherapy. Here, we asked whether lymphangiogenesis influences the immune response and anti-tumor efficacy elicited by RT. We employed two variants of the aggressive B16F10 melanoma model: a variant that was transduced to overexpress the lymphangiogenic factor VEGF-C (B16-VEGF-C), and a mock-transduced (B16-ctrl) variant. Tumor-bearing animals were treated by ablative doses of localized RT and monitored for tumor growth and survival, while anti-tumor immune responses were assessed by flow cytometry and ELISA. We observed that the therapeutic efficacy of RT was greater in B16-VEGF-C melanomas compared to B16-ctrl, as evidenced by a significant inhibition of tumor growth and extended animal survival. In line with this finding, B16-VEGF-C melanomas exhibited a significantly higher 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. To gain further insight, we assessed the tumor infiltration and activation status of antigen-presenting cells. Consistent with the observed T cell response, we found that both dendritic cells and macrophages exhibited a greater expression of co-stimulatory molecules in B16-VEGF-C melanomas after RT. 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. Lymphangiogenesis augments the anti-tumor efficacy of radiotherapy in mouse melanoma [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 2253.