Abstract 4585: Tumor lymphangiogenesis sensitizes melanomas to the immunological effects of radiotherapy but also disrupts the local lymphatic vasculature

Tumor lymphangiogenesis is typically associated with cancer progression and metastasis. However, recent studies from our group have demonstrated that tumor lymphangiogenesis promotes intratumor T cell infiltration and potentiates the efficacy of a wide range of immunotherapies in melanoma-bearing mice as well as patients undergoing checkpoint blockade. Radiotherapy (RT) can also induce immunogenic tumor cell death, so we investigated whether lymphangiogenic tumors would yield more immunogenic responses to RT than non-lymphangiogenic tumors. Here, we compared effects of RT in mice bearing B16-F10 melanomas expressing either a control vector (B16-Ctrl) or overexpression the lymphangiogenic factor VEGF-C (B16-VC), where lymphatic vessels were significantly increased in number and size compared to B16-Ctrl tumors. First, we find that B16-VC regress faster than B16-CT after RT (either a single 20 Gy dose or two 15 Gy doses), and that this regression was correlated with enhanced CD8+ T cell activity. On the other hand, lymphatic endothelial cells (LECs) can be more sensitive to damage from RT if they are undergoing lymphangiogenesis. We found that irradiated B16-VC tumors showed higher levels of intra-lymphatic fibrin. Consistent with this, LECs in the irradiated B16-VC tumors expressed higher levels of tissue factor and caspase-3, which correlated with the degree of lymphatic clotting. Fibrin clotting was also observed in the subcapsular sinus of the draining lymph nodes of irradiated B16-VC tumors. These findings highlight the complex role of tumor lymphangiogenesis in radiotherapy responses, where they may potentiate acute anti-tumor immune responses but may also cause localized damage of the vasculature, potentially leading to increased metastasis. Further studies are needed to investigate therapeutic targets to inhibit lymphatic coagulation and look at its effects on cancer immunotherapy and metastasis. Citation Format: Anish Mukherjee, Nikolaos Mitrousis, Mari Stella Sasso, Margo MacDonald, Ainhoa Arina, Phillip Ang, Ariana Baginski, J. Emiliano G. Medellin, Ralph R. Weichselbaum, Melody A. Swartz. Tumor lymphangiogenesis sensitizes melanomas to the immunological effects of radiotherapy but also disrupts the local lymphatic vasculature. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abst