Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Sep;43(9):728-740.
doi: 10.1016/j.it.2022.07.002. Epub 2022 Aug 3.

High endothelial venules as potential gateways for therapeutics

Bilal Hussain  1 , Vivek Kasinath  1 , Gabriel P Ashton-Rickardt  2 , Thomas Clancy  3 , Kenji Uchimura  4 , George Tsokos  5 , Reza Abdi  6
Affiliations
Review

High endothelial venules as potential gateways for therapeutics

Bilal Hussain et al. Trends Immunol. 2022 Sep.

Abstract

High endothelial venules (HEVs) are specialized blood vessels that support the migration of lymphocytes from the bloodstream into lymph nodes (LNs). They are also formed ectopically in mammalian organs affected by chronic inflammation and cancer. The recent arrival of immunotherapy at the forefront of many cancer treatment regimens could boost a crucial role for HEVs as gateways for the treatment of cancer. In this review, we describe the microanatomical and biochemical characteristics of HEVs, mechanisms of formation of newly made HEVs, immunotherapies potentially dependent on HEV-mediated T cell homing to tumors, and finally, how HEV-targeted therapies might be used as a complementary approach to potentially shape the therapeutic landscape for the treatment of cancer and immune-mediated diseases.

Keywords: cancer immunology; high endothelial venule; lymph node; nanomedicine; nanoparticles; transplantation.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors have no interests to declare.

Figures

Figure 1.
Figure 1.. Morphological features of HEVs.
(A) Fluorescence micrograph of PNAd+ HEVs (green) in the mouse LN demonstrates thickness and presence of characteristic pockets (arrows) of the HEV (nuclear stain DAPI, blue). (B) Fluorescence micrograph displays HEVs (green, arrows) in the paracortex (T cell zone) of the mouse LN, surrounded by CD3+ T cells (red). (C) Electron micrograph of HEV in mouse LN shows orientation of lymphocytes (L), HECs (E), and pericytes (P).
Figure 2.
Figure 2.. Diagram of HEV-targeted drug delivery to metastatic cancer.
Drugs can be delivered simultaneously to three important treatment sites in cancers like metastatic human PDAC in humanized mouse models—the primary tumor (top left), the tumor-draining lymph nodes (top right), and distant metastatic lesions (bottom right)—through antibody-drug conjugates[10] or encapsulation inside antibody-conjugated nanoparticles that bind to PNAd on HEVs. Some off-target drug accumulation in naïve lymph nodes (bottom left) and secondary lymphoid organs will also be expected, due to the presence of HEVs.
See this image and copyright information in PMC

References

    1. Singh SK and Singh R (2022) Nanotherapy: targeting the tumour microenvironment. Nat Rev Cancer 22 (5), 258. - PubMed
    1. Fletcher AL et al. (2011) Lymph node stroma broaden the peripheral tolerance paradigm. Trends Immunol 32 (1), 12–8. - PMC - PubMed
    1. Drayton DL et al. (2006) Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol 7 (4), 344–53. - PubMed
    1. Ager A. (1998) High Endothelial Venules. In Encyclopedia of Immunology (Second Edition) (Delves PJ ed), pp. 1093–1101, Elsevier.
    1. Weinstein AM and Storkus WJ (2016) Biosynthesis and Functional Significance of Peripheral Node Addressin in Cancer-Associated TLO. Front Immunol 7, 301. - PMC - PubMed

Publication types