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.