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ARTICLEhttps://doi.org/10.1038/s41467-022-30063-OPENExtracellular vimentin mimics VEGF and it is a target for anti-angiogenic immunotherapyJudy R. van Beijnum1,two,three, Elisabeth J. M. Huijbers one,2, Karlijn van Loon 1,two, Athanasios Blanas1,2, Parvin Akbari1,2, Arno Roos4, Tse J. Wong1,two, Stepan S. Denisov5, Tilman M. Hackeng5, Connie R. NOX4 drug Jimenez2,6, Patrycja Nowak-Sliwinska7,eight,9 Arjan W. Griffioen 1,two,1234567890():,;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 as a result of variety III unconventional secretion mechanisms. Extracellular vimentin is pro-angiogenic and functionally mimics VEGF action, even though concomitantly acting as inhibitor of leukocyte-endothelial interactions. Antibody targeting of extracellular vimentin demonstrates inhibition of angiogenesis in vitro and in vivo. Productive and secure inhibition of angiogenesis and tumor development in several preclinical and clinical studies is demonstrated using a vaccination method towards extracellular vimentin. Focusing on vimentin induces a pro-inflammatory condition in the tumor, exemplified by induction from the endothelial adhesion molecule ICAM1, suppression of PD-L1, and altered immune cell profiles. Our findings demonstrate that extracellular vimentin contributes to immune suppression and functions as being a vascular immune checkpoint molecule. Focusing on of extracellular vimentin presents consequently an anti-angiogenic immunotherapy system against cancer.UMC place Vrije Universiteit Amsterdam, Angiogenesis Laboratory, Division of Healthcare Oncology, Amsterdam, The Netherlands. Center Amsterdam, Cancer Biology and Immunonology, Amsterdam, The Netherlands. three CimCure BV, The Hague, The Netherlands. four Veterinary Referral Centre Korte Akkeren, Gouda, The Netherlands. five Division of Biochemistry, Cardiovascular Investigate Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands. six Amsterdam UMC area Vrije Universiteit Amsterdam, Oncoproteomics Laboratory, Division of Medical Oncology, Amsterdam, The Netherlands. seven School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, Geneva, Switzerland. eight Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland. 9 Translational Investigate Center in Oncohaematology, University of Geneva, Geneva, Switzerland. electronic mail: [email protected] Cancer1 AmsterdamNATURE COMMUNICATIONS (2022)13:2842 https://doi.org/10.1038/s41467-022-30063-7 www.nature.com/naturecommunicationsARTICLENATURE COMMUNICATIONS https://doi.org/10.1038/s41467-022-30063-he tumor microenvironment (TME) is extremely immunosuppressive, that is heavily mediated through the aberrant tumor vasculature1,2. As a consequence of constant expo.
