Extracellular vimentin mimics VEGF and is a target for anti-angiogenic immunotherapy

Anti-angiogenic cancer therapies possess immune-stimulatory properties by counteracting pro-angiogenic molecular mechanisms. We report that tumor endothelial cells ubiquitously overexpress and secrete the intermediate filament protein vimentin through type III unconventional secretion mechanisms. Ex...

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Bibliographic Details
Published in:	Nature communications 2022-05, Vol.13 (1), p.2842-2842, Article 2842
Main Authors:	van Beijnum, Judy R, Huijbers, Elisabeth J M, van Loon, Karlijn, Blanas, Athanasios, Akbari, Parvin, Roos, Arno, Wong, Tse J, Denisov, Stepan S, Hackeng, Tilman M, Jimenez, Connie R, Nowak-Sliwinska, Patrycja, Griffioen, Arjan W
Format:	Article
Language:	eng
Subjects:	Angiogenesis Antiangiogenics Antibodies Cancer Endothelial cells Immune checkpoint Immune system Immunotherapy Inflammation Intercellular adhesion molecule 1 Leukocytes Molecular modelling PD-L1 protein Tumors Vaccination Vascular endothelial growth factor Vimentin
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Summary:	Anti-angiogenic cancer therapies possess immune-stimulatory properties by counteracting pro-angiogenic molecular mechanisms. We report that tumor endothelial cells ubiquitously overexpress and secrete the intermediate filament protein vimentin through type III unconventional secretion mechanisms. Extracellular vimentin is pro-angiogenic and functionally mimics VEGF action, while concomitantly acting as inhibitor of leukocyte-endothelial interactions. Antibody targeting of extracellular vimentin shows inhibition of angiogenesis in vitro and in vivo. Effective and safe inhibition of angiogenesis and tumor growth in several preclinical and clinical studies is demonstrated using a vaccination strategy against extracellular vimentin. Targeting vimentin induces a pro-inflammatory condition in the tumor, exemplified by induction of the endothelial adhesion molecule ICAM1, suppression of PD-L1, and altered immune cell profiles. Our findings show that extracellular vimentin contributes to immune suppression and functions as a vascular immune checkpoint molecule. Targeting of extracellular vimentin presents therefore an anti-angiogenic immunotherapy strategy against cancer.
ISSN:	2041-1723 2041-1723