Abstract
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.
Highlights
The immune system plays a critical role in tumor surveillance [1], patient's clinical outcome [2], and therapeutic response [3, 4]
We investigated the presence of High endothelial venules (HEV) within various human primary solid tumors and their association with lymphocyte infiltration, immune orientation, and clinical outcome in breast cancer
To define the functional consequence of tumor HEVs, we focused on a retrospective cohort of 146 primary, invasive, nonmetastatic breast cancer patients operated at the Institute Claudius Regaud (ICR) between 1997 and 1998
Summary
The immune system plays a critical role in tumor surveillance [1], patient's clinical outcome [2], and therapeutic response [3, 4]. The presence of high numbers of tumorinfiltrating lymphocytes, T cells, has been found to be a major predictor of favorable clinical outcome in several solid cancers, including colorectal [5,6,7], lung [8], and ovarian carcinomas [9,10,11]. The blood vessels and mechanisms governing the recruitment of lymphocytes into tumors remain poorly understood. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Authors' Affiliations: 1CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale); 2UPS, IPBS, and 3UPS, CPTP, Universite de Toulouse; 4Institut Claudius Regaud; and 5INSERM, U563, Centre de Physiopathologie de Toulouse-Purpan, Toulouse, France
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