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High endothelial venules (HEVs), specialized blood vessels for lymphocyte migration

High Endothelial Venules (HEVs) mediate lymphocyte extravasation into lymphoid organs. A few years ago, we discovered that blood vessels with HEV characteristics are also frequently found in solid tumors, in association with cytotoxic T cell infiltration. Contrary to the dogma that blood vessels facilitate tumor growth, tumor-associated HEVs (TA-HEVs) correlated with favorable clinical outcome in breast cancer.

HEVs, portals of entry for lymphocytes into lymphoid organs

HEVs are anatomically distinct post-capillary venules that function as portals of entry for lymphocytes into lymph nodes and other secondary lymphoid organs1,2. HEV-mediated recruitment of lymphocytes is a very efficient process since it is estimated that, every second, 5 million lymphocytes migrate through HEVs of the body1. The endothelial cells lining HEVs have a plump, almost cuboïdal appearance, and express sulfated ligands for lymphocytes, recognized by the HEV-specific antibody MECA-791,2. In 1995, we developed a specific protocol for the isolation of HEV endothelial cells from fresh human lymphoid organs3 that opened the way to the molecular characterization of these specialized endothelial cells, including the discovery and characterization of 17 novel human genes by our team over the past 20 years (Hevin, PAPSS1, SUT1, SLC26A7, SLC26A11, THAP1 to THAP11, NF-HEV/IL-33).

In 2011, we made a major breakthrough in our understanding of the mechanisms regulating HEV differentiation by demonstrating the critical role of dendritic cells in this process4. After in vivo depletion of CD11c+ dendritic cells in adult mice, we observed a striking downregulation of HEV-specific marker MECA-79 and HEV-specific genes (GlyCAM-1, FucT-VII, GlcNAc6ST-2) in lymph nodes. Intravital microscopy analyses revealed striking alterations in lymphocyte/HEV interactions, which resulted in an inhibition of HEV-mediated lymphocyte recruitment into lymph nodes4. Dendritic cells expressed lymphotoxin and dendritic cell-derived lymphotoxin was found to be essential for HEV-mediated lymphocyte recruitment in vivo4. Together, our findings revealed a previously unsuspected and important function of dendritic cells in the control of HEV phenotype and function.

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HEVs are portals of entry for lymphocytes into lymphoid tissues.

HEV endothelial cells exhibit a plump morphology, very different from the flat morphology of ‘classical’ endothelial cells. Lymphocytes extravasate through HEVs via a multistep adhesion cascade (rolling, sticking, crawling, transmigration). The two-photon microscopy image shows a post-capillary HEV (green, fluorescent mAb MECA-79) in the lymph node microcirculation (red, rhodamine-conjugated dextran).maintenance of HEV EC differentiation, which is one of the major objectives of our team, may thus allow the development of novel therapeutic approaches for both chronic inflammatory diseases and cancer.

Tumor-associated HEVs (TA-HEVs) contribute to the ‘fight’ against cancer

We discovered that blood vessels with HEV characteristics (plump endothelial cells expressing HEV-specific marker MECA-79) are frequently found in the stroma of human solid tumors including melanomas, breast, ovarian and lung carcinomas5-7. In both breast tumors (n = 273)5,7 and primary melanomas (n = 225)6, the density of HEVs was highly correlated with the density of tumor-infiltrating CD3+ and CD8+ cytotoxic T cells, indicating that tumor-associated HEVs (TA-HEVs) may function as major portals of entry for cytotoxic T cells into human solid tumors.

We found that a high density of HEVs in the tumor microenvironment independently conferred a lower risk of relapse and significantly correlated with breast cancer patient longer survival5. In addition, we found correlations between high densities of TA-HEVs and favourable clinical parameters in primary melanoma6. Interestingly, TA-HEVs may limit metastasis (probably through their capacity to recruit, into the primary tumor, naïve and memory T cells able to fight tumor cells at distant sites), since a high density of HEVs in breast tumors was associated with longer metastasis-free survival5. These studies introduced the novel concept that ‘blood vessels in the tumor microenvironment are not all the same and that some types of blood vessels (i.e. TA-HEVs) can contribute to tumor suppression rather than tumor growth’.

This concept could have broad applications for many types of human solid tumors and novel therapeutic strategies based on the modulation of TA-HEVs could have a major impact on clinical outcome of cancer patients.

 

Image Figure 2.pngTumor-associated HEVs (TA-HEVs) in human cancer and their proposed role as portals of entry  for lymphocytes into human breast tumors. TA-HEVs are lined by plump endothelial cells positive for HEV-specific marker MECA-79 and surrounded by lymphocytes. A high density of TA-HEVs correlates with high levels of CD3+ T cells, CD8+ cytotoxic T cells and CD20+ B cells infiltration in the breast tumor microenvironment.

 

References:

  1. Girard, J. P. & Springer, T. A. High endothelial venules (HEVs): specialized endothelium for lymphocyte migration. Immunol Today 16, 449-457 (1995).
  2. Girard, J. P., Moussion, C. & Forster, R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat Rev Immunol 12, 762-773, doi:10.1038/nri3298 (2012).
  3. Girard, J. P. & Springer, T. A. Cloning from purified high endothelial venule cells of hevin, a close relative of the antiadhesive extracellular matrix protein SPARC. Immunity 2, 113-123 (1995).
  4. Moussion, C. & Girard, J. P. Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules. Nature 479, 542-546 (2011).
  5. Martinet, L. et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res 71, 5678-5687, doi:10.1158/0008-5472.CAN-11-0431 (2011).
  6. Martinet, L. et al. High endothelial venules (HEVs) in human melanoma lesions: major gateways for tumor-infiltrating lymphocytes. OncoImmunology 1, 829-839 (2012).
  7. Martinet, L. et al. High Endothelial Venule Blood Vessels for Tumor-Infiltrating Lymphocytes Are Associated with Lymphotoxin beta-Producing Dendritic Cells in Human Breast Cancer. J Immunol 191, 2001-2008, doi:10.4049/jimmunol.1300872 (2013).