High Endothelial Venule Blood Vessels for Tumor-Infiltrating Lymphocytes Are Associated with Lymphotoxin β–Producing Dendritic Cells in Human Breast Cancer

Abstract

Blood vessels and tumor angiogenesis are generally associated with tumor growth and poor clinical outcome of cancer patients. However, we recently discovered that some blood vessels present within the tumor microenvironment can be associated with favorable prognosis. These vessels, designated tumor high endothelial venules (HEVs), appear to facilitate tumor destruction by allowing high levels of lymphocyte infiltration into tumors. In this study, we investigated the mechanisms regulating HEV blood vessels in human breast cancer. We found that lymphotoxin β was overexpressed in tumors containing high densities of HEVs (HEV(high)) and correlated to DC-LAMP, a marker of mature DCs. DCs were the main producers of lymphotoxin β in freshly resected HEV(high) breast tumor samples, and the density of DC-LAMP(+) DCs clusters was strongly correlated with the density of tumor HEVs, T and B cell infiltration, and favorable clinical outcome in a retrospective cohort of 146 primary invasive breast cancer patients. Densities of tumor HEVs and DC-LAMP(+) DCs were strongly reduced during breast cancer progression from in situ carcinoma to invasive carcinoma, suggesting that loss of tumor HEVs is a critical step during breast cancer progression. Finally, an increase in the infiltration of regulatory T cells was observed in HEV(high) breast tumors, indicating that tumor HEVs can develop in the presence of regulatory T cells. Together, our results support a key role for DCs and DC-derived lymphotoxin in the formation of tumor HEVs. These findings are important because novel therapeutic strategies based on the modulation of tumor HEVs could have a major impact on clinical outcome of cancer patients.