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Link to original content: https://pubmed.ncbi.nlm.nih.gov/33956259/
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Review
. 2021 Nov;24(4):719-753.
doi: 10.1007/s10456-021-09792-8. Epub 2021 May 6.

High endothelial venules (HEVs) in immunity, inflammation and cancer

Lucas Blanchard  1 , Jean-Philippe Girard  2
Affiliations
Review

High endothelial venules (HEVs) in immunity, inflammation and cancer

Lucas Blanchard et al. Angiogenesis. 2021 Nov.

Abstract

High endothelial venules (HEVs) are specialized blood vessels mediating lymphocyte trafficking to lymph nodes (LNs) and other secondary lymphoid organs. By supporting high levels of lymphocyte extravasation from the blood, HEVs play an essential role in lymphocyte recirculation and immune surveillance for foreign invaders (bacterial and viral infections) and alterations in the body's own cells (neoantigens in cancer). The HEV network expands during inflammation in immune-stimulated LNs and is profoundly remodeled in metastatic and tumor-draining LNs. HEV-like blood vessels expressing high levels of the HEV-specific sulfated MECA-79 antigens are induced in non-lymphoid tissues at sites of chronic inflammation in many human inflammatory and allergic diseases, including rheumatoid arthritis, Crohn's disease, allergic rhinitis and asthma. Such vessels are believed to contribute to the amplification and maintenance of chronic inflammation. MECA-79+ tumor-associated HEVs (TA-HEVs) are frequently found in human tumors in CD3+ T cell-rich areas or CD20+ B-cell rich tertiary lymphoid structures (TLSs). TA-HEVs have been proposed to play important roles in lymphocyte entry into tumors, a process essential for successful antitumor immunity and lymphocyte-mediated cancer immunotherapy with immune checkpoint inhibitors, vaccines or adoptive T cell therapy. In this review, we highlight the phenotype and function of HEVs in homeostatic, inflamed and tumor-draining lymph nodes, and those of HEV-like blood vessels in chronic inflammatory diseases. Furthermore, we discuss the role and regulation of TA-HEVs in human cancer and mouse tumor models.

Keywords: Cancer immunology; Chronic inflammatory diseases; High endothelial venules (HEVs); Lymphocyte trafficking; Tertiary lymphoid structures; Tumor blood vessels.

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Figures

Fig. 1
Fig. 1
HEVs in secondary lymphoid organs. a Lymph nodes are encapsulated lymphoid organs subdivided into three regions: the cortex, the paracortex and the medulla. Blood enters the LN through a main feeding artery that branches into arterioles and capillaries in the medulla and the paracortex, respectively. Then, blood flows from the capillary beds into the post-capillary HEVs that are located in the T cell zone of the LN. Finally, blood flows through medullary venules and leave the LN via a collecting vein. Immune cells enter the LN through HEVs or afferent lymphatic vessels and exit via the efferent lymphatic vessel in the medulla. b HEVs in human tonsils. MECA-79 staining reveals the “plump” cuboidal morphology of HEV endothelial cells (HECs) (Left). MECA-79+ HECs express high levels of the nuclear cytokine IL-33 [7] (Right). The gene encoding IL-33 was originally discovered as a gene highly expressed in MECA-79+ HECs isolated from human tonsils, and IL-33 was thus initially designated as “nuclear factor from high endothelial venules” (NF-HEV) [8, 9]
Fig. 2
Fig. 2
HEV-mediated recruitment of lymphocytes in peripheral lymph nodes. a Naive T and B cells circulating in the blood tether and roll on HEV walls. Subsequently, rolling lymphocytes interact with chemokines immobilized on the HEV luminal surface. Chemokine receptor-dependent signaling induces activation of lymphocyte integrins that mediate firm binding (sticking) to their counter-receptors on HEV endothelium. Then, lymphocytes crawl on the HEV surface for a few minutes before transmigrating across the HEV endothelium via “exit ramps”. Some lymphocytes also accumulate transiently in “HEV pockets”. b Naive lymphocytes roll on HEV endothelium through the binding of L-selectin to 6-sulfo sialyl Lewis X motifs decorating both O-glycans and N-glycans on HEV sialomucins (Left). Representation of a bi-antennary O-linked glycan on a HEV sialomucin (Right). Both extended core-1 and core-2 branch structures can display the 6-sulfo sialyl Lewis X motif (highlighted in yellow). The 6-sulfo sialyl Lewis X motif is a tetra-saccharide composed of N-acetylglucosamine (GlcNAc), galactose (Gal), sialic acid (Sia) and fucose (Fuc), linked through N-acetylgalactosamine (GalNAc) to a serine (Ser) or threonine (Thr) residue of the core HEV sialomucin protein. α and β linkages of the saccharide units are shown. The epitope of MECA-79 (highlighted in blue) is a component of the core-1 extension. The C-6 sulfation (red SO3-) of N-acetylglucosamine, that is referred to as “6-sulfo”, is required for both L-selectin and MECA-79 recognition. Black rectangles indicate genes encoding enzymes involved in the synthesis of the 6-sulfo sialyl Lewis X motif. c Naive lymphocytes rolling on HEV walls interact with chemokines that are presented by heparan sulfate such as CCL21. Signaling through CCR7 induces conformational changes in the lymphocyte integrin LFA1, which mediate binding to ICAM1 and ICAM2 on the HEV endothelium, leading to firm arrest (sticking) of the lymphocytes. Following a rapid step of crawling, lymphocytes eventually transmigrate through HEVs to enter the lymphoid tissue
Fig. 3
Fig. 3
HEVs in inflamed lymph nodes. During an immune challenge, the HEV network expands, contributing to the increase in size and cellularity of the reactive LN (Top). HECs in reactive LNs are phenotypically different from HECs in homeostatic LNs at steady state (Bottom). scRNA-seq analyses revealed the precise phenotypes of homeostatic and inflamed LN HECs [53]. Several genes encoding inflammatory proteins are upregulated (P- and E-selectins, CXCL9), resulting in the recruitment of novel immune cells such as activated lymphocytes and myeloid cells. Importantly, the recruitment of naïve lymphocytes in inflamed LNs is still efficient despite downregulation of mature HEV genes, probably because levels of MECA-79 antigens and chemokine CCL21 remain very high
Fig. 4
Fig. 4
HEV-like blood vessels in chronic inflammation. a A MECA-79+ HEV-like blood vessel in the inflamed synovium from a patient suffering from RA. Endothelial cells exhibit a “plump” cuboidal morphology. Staining with MECA-79 is more intense on the side of the vessel in contact with the immune infiltrate (arrow). b During acute inflammation, MECA-79− blood vessels are able to recruit activated lymphocytes and myeloid cells (Left). Prolonged inflammatory signals (such as LTα3) trigger TNFR1 signaling that induces expression of MECA-79 antigens on post-capillary venules lined by flat endothelial cells, during the initial stages of chronic inflammation (Middle). Maintenance of chronic inflammation and subsequent activation of LTβR signaling induce additional maturation and acquisition of a fully mature HEV-like phenotype that is associated with increased luminal expression of MECA-79 antigens, cuboidal morphology and enhanced recruitment of naive lymphocytes (Right)
Fig. 5
Fig. 5
TA-HEVs and T cell infiltration in human primary melanoma and breast cancer. a MECA-79+ TA-HEVs in human primary melanoma. TA-HEVs are present in a regressing tumor area infiltrated by CD3+ T cells. b MECA-79+ TA-HEVs in human primary breast cancer. TA-HEVs are present in tumor areas infiltrated by CD3+ T cells. MECA-79 staining is more intense on the side of the blood vessels in contact with the lymphocytic infiltrate (arrows). See original references from Martinet, Garrido et al. [28, 29]
Fig. 6
Fig. 6
TA-HEVs are present in both T cell-rich areas and B cell-rich TLSs. a MECA-79+ TA-HEVs in human primary breast cancer. TA-HEVs are present in a tumor area highly infiltrated by CD20+ B cells. These lymphoid aggregates enriched in B cells are designated B cell-rich TLSs. b MECA-79+ TA-HEVs in human primary melanoma. TA-HEVs are present in a tumor area highly infiltrated by CD3+ T cells and by some CD20+ B cells with no apparent organization into TLSs. See original references from Martinet, Garrido et al. [28, 29]
Fig. 7
Fig. 7
Therapeutic induction of TA-HEVs for cancer therapy. Induction of MECA-79+ TA-HEVs in the tumor microenvironment may increase infiltration of various subsets of CD8+ and CD4+ T cells, as well as CD20+ B cells, and may improve antitumor immunity and efficacy of various cancer treatments, including immunotherapies with immune checkpoint inhibitors, adoptive T cell therapy or vaccines, but also potentially targeted therapies and conventional cancer therapies (radiotherapy, chemotherapy)
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