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

Judy R. Beijnum, Elisabeth J. M. Huijbers, Karlijn Loon, Athanasios Blanas, Parvin Akbari, Arno Roos, Tse J. Wong, Stepan S. Denisov, Tilman M. Hackeng, Connie R. Jimenez, Patrycja Nowak-Sliwinska and Arjan W. Griffioen ()
Additional contact information
Judy R. Beijnum: Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
Elisabeth J. M. Huijbers: Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
Karlijn Loon: Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
Athanasios Blanas: Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
Parvin Akbari: Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
Arno Roos: Veterinary Referral Centre Korte Akkeren
Tse J. Wong: Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
Stepan S. Denisov: University of Maastricht
Tilman M. Hackeng: University of Maastricht
Connie R. Jimenez: Cancer Biology and Immunonology
Patrycja Nowak-Sliwinska: University of Geneva
Arjan W. Griffioen: Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30063-7

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