Triple-negative breast cancer (TNBC) has a higher relapse rate and fewer treatment options compared to other molecular subtypes of breast cancer. Cancer immunotherapies are currently being investigated as a new treatment modality in TNBC to improve survival rates. However, a significant subset of patients still does not respond to these therapies. A better understanding of the tumor microenvironment in breast cancer is needed to identify new biomarkers to stratify patients who would benefit from cancer immunotherapies. As a critical component of the immune system, the lymphatics have been shown to regulate anti-tumor immune responses in multiple tumor types, including in melanoma and glioblastoma. Here, I investigated the role of tumor lymphangiogenesis - the process of lymphatic vessel remodeling and expansion - in shaping anti-tumor immunity in breast cancer. In order to model tumor lymphangiogenesis in vivo, we transduced murine models of triple-negative mammary carcinoma to over-express the pro-lymphangiogenic vascular endothelial growth factor-C (VEGF-C). We show that tumor lymphangiogenesis increases recruitment of CD4+ T cells and macrophages into the tumor microenvironment. Upon treatment with cancer immunotherapies, namely checkpoint inhibitors (CPI) and an agonist of Stimulator of Interferon Genes (STING) pathway, lymphangiogenic 4T1 tumors demonstrate improved responsiveness to the treatment and prolonged survival. The increase in the levels of various chemokines after immunotherapy treatment leads to recruitment of various immune cells, including cross-presenting dendritic cells (DCs) and interferon- (IFN) secreting CD8+ T cells. Furthermore, after treatment with a combination of CPI and STING agonist, the potent systemic anti-tumor immunity in the lymphangiogenic 4T1 tumor-bearing mice reduces the spontaneous lung metastasis in 4T1 tumor-bearing mice. The beneficial effect of tumor lymphangiogenesis is dependent on CD4+ T cells and macrophages, as their depletion abrogates the observed phenotype. Consistent with the murine studies, expression of VEGF-C positively correlates with CD4 and macrophage gene expressions in human triple-negative breast tumors. These results reveal that tumor lymphangiogenesis improves responsiveness to cancer immunotherapies in mice and suggests that patients with increased tumor lymphatics may further benefit from these therapies.



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