4.5 Article

CD73 contributes to anti-inflammatory properties of afferent lymphatic endothelial cells in humans and mice

Journal

EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 51, Issue 1, Pages 231-246

Publisher

WILEY
DOI: 10.1002/eji.201948432

Keywords

CD73; dendritic cells; lymphatic endothelial cells; siRNA; vascular biology

Categories

Funding

  1. University of Turku
  2. Angstrombo Akademi University
  3. Biocenter Finland
  4. Sigrid Juselius Foundation
  5. Finnish Cultural Foundation
  6. Wihuri Foundation
  7. Maud Kuistila Foundation
  8. Turku University Foundation
  9. K. Albin Johansson Foundation
  10. Ella and Georg Ehrnrooth foundation
  11. Finnish Cancer Foundation
  12. 7th Framework Programme for Research and Technological Development (EU-FP7 TumAdoR)
  13. European Research Council (ERC) starting grant
  14. Academy of Finland

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CD73 plays an unknown role in dampening immune responses on afferent lymphatics, as revealed by this study. Knocking out or suppressing CD73 leads to upregulation of inflammation-associated genes on lymphatic endothelial cells and a more pro-inflammatory phenotype of interacting dendritic cells in vitro and in vivo. Anti-CD73 antibodies have negligible effects on gene expression of lymphatic- and blood-endothelial cells, indicating a low likelihood of endothelial cell-related adverse effects with CD73 targeting therapeutic antibodies.
CD73 is an important ectoenzyme responsible for the production of extracellular adenosine. It is involved in regulating inflammatory responses and cell migration and is overexpressed in various cancers. The functions of CD73 in blood endothelial cells are understood in detail, but its role on afferent lymphatics remains unknown. Moreover, anti-CD73 antibodies are now used in multiple clinical cancer trials, but their effects on different endothelial cell types have not been studied. This study reveals that a previously unknown role of CD73 on afferent lymphatics is to dampen immune responses. Knocking it out or suppressing it by siRNA leads to the upregulation of inflammation-associated genes on lymphatic endothelial cells and a more pro-inflammatory phenotype of interacting dendritic cells in vitro and in vivo. In striking contrast, anti-CD73 antibodies had only negligible effects on the gene expression of lymphatic- and blood-endothelial cells. Our data thus reveal new functions of lymphatic CD73 and indicate a low likelihood of endothelial cell-related adverse effects by CD73 targeting therapeutic antibodies.

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