Abstract B97: the Immunomodulatory Roles of Tumor-Associated Lymphatics in Triple-Negative Breast Cancer

Abstract During cancer development, growth and remodeling of lymphatic vessels—termed lymphangiogenesis—is associated with increased metastasis rate. However, our group has recently shown that lymphangiogenesis can also increase tumor immune infiltration and subsequently enhance the responsiveness to immunotherapies in melanoma. However, the role of lymphangiogenesis in antitumor immunity in breast cancer remains unexplored. Moreover, despite the success of immunotherapies in different cancer types, their translation into the treatment of breast cancer has remained challenging. Here, we investigated the role of tumor lymphangiogenesis in immune cell infiltration and responsiveness to immunotherapy in a murine triple-negative breast tumor model. Spontaneously metastatic 4T1 tumor cells were transduced to overexpress the pro-lymphangiogenic growth factor VEGF-C to model tumor lymphangiogensis in vivo. We confirmed that VEGF-C overexpressing tumors were more lymphangiogenic than control ones, as assessed by flow cytometry and immunohistochemistry analyses. As previously reported, tumor VEGF-C signaling also increased the metastatic burden in the lungs. Crucially, lymphangiogenic tumors were infiltrated with increased levels of immune cells, including CD4 T cells and macrophages. Upon treatment with an agonist of the stimulator of interferon genes (STING) pathway, lymphangiogenic 4T1 tumors responded more favorably to the therapy compared to the control tumors, as indicated by a reduced tumor growth in the VEGF-C group. Furthermore, gene expression analysis of human triple-negative breast tumor samples from The Cancer Genome Atlas revealed positive correlations between VEGFC expression and CD4 T-cell and macrophage gene expressions. Taken together, these data suggest that in triple-negative breast cancer, similarly to melanoma, VEGF-C signaling is beneficial to the primary tumor microenvironment upon combination with proper immunotherapy despite promoting metastasis in untreated tumors. Citation Format: Peyman Hosseinchi, Lambert Potin, Aslan Mansurov, Léa Maillat, Jeffrey A. Hubbell, Melody A. Swartz. The immunomodulatory roles of tumor-associated lymphatics in triple-negative breast cancer [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 B97.