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

Author

Listed:
  • Judy R. Beijnum

    (Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
    Cancer Biology and Immunonology
    CimCure BV)

  • Elisabeth J. M. Huijbers

    (Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
    Cancer Biology and Immunonology)

  • Karlijn Loon

    (Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
    Cancer Biology and Immunonology)

  • Athanasios Blanas

    (Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
    Cancer Biology and Immunonology)

  • Parvin Akbari

    (Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
    Cancer Biology and Immunonology)

  • Arno Roos

    (Veterinary Referral Centre Korte Akkeren)

  • Tse J. Wong

    (Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
    Cancer Biology and Immunonology)

  • Stepan S. Denisov

    (University of Maastricht)

  • Tilman M. Hackeng

    (University of Maastricht)

  • Connie R. Jimenez

    (Cancer Biology and Immunonology
    Amsterdam UMC location Vrije Universiteit Amsterdam, Oncoproteomics Laboratory, Department of Medical Oncology)

  • Patrycja Nowak-Sliwinska

    (University of Geneva
    University of Geneva
    University of Geneva)

  • Arjan W. Griffioen

    (Amsterdam UMC location Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Department of Medical Oncology
    Cancer Biology and Immunonology
    CimCure BV)

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.

Suggested Citation

  • 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-Sli, 2022. "Extracellular vimentin mimics VEGF and is a target for anti-angiogenic immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30063-7
    DOI: 10.1038/s41467-022-30063-7
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    References listed on IDEAS

    as
    1. Sara M. Weis & David A. Cheresh, 2005. "Pathophysiological consequences of VEGF-induced vascular permeability," Nature, Nature, vol. 437(7058), pages 497-504, September.
    2. Bianca Cioni & Anniek Zaalberg & Judy R. Beijnum & Monique H. M. Melis & Johan Burgsteden & Mauro J. Muraro & Erik Hooijberg & Dennis Peters & Ingrid Hofland & Yoni Lubeck & Jeroen Jong & Joyce Sander, 2020. "Androgen receptor signalling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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