The mechanisms governing infiltration of lymphocytes into
tumors remain poorly characterized, in spite of the critical impact of these cells on patient prognosis and therapeutic responses. High endothelial venules (HEV) are blood vessels found in lymphoid tissues, specialized in lymphocyte recruitment, but their implications in human
cancer are unknown. In this article, we report the presence of
MECA 79(+) blood vessels displaying all the phenotypic characteristics of HEVs in most of the 319 human primary solid
tumors, including
melanomas, breast, ovarian, colon, and lung
carcinomas, analyzed.
Tumor HEVs were specifically located within lymphocyte-rich areas, and their density within the
tumor stroma was a strong predictor of infiltration by CD3(+) and CD8(+) T cells as well as B cells. Large-scale flow cytometric and quantitative
reverse transcriptase-PCR analyses in freshly operated
breast tumors revealed that high densities of
tumor HEVs correlated with increased naive, central memory and activated effector memory T-cell infiltration and upregulation of genes related to T-helper 1 adaptive immunity and T-cell cytotoxicity. Finally, in a retrospective cohort of 146 invasive
breast cancer patients, we found that high densities of
tumor HEVs independently conferred a lower risk of relapse and significantly correlated with longer
metastasis-free, disease-free, and overall survival rates. Together, our findings suggest that
tumor HEVs function as major gateways for lymphocyte infiltration into human
tumors, and may represent attractive targets for
cancer diagnosis and
therapy.