TY - JOUR
T1 - Extracellular vimentin mimics VEGF and is a target for anti-angiogenic immunotherapy
AU - van Beijnum, Judy R.
AU - Huijbers, Elisabeth J. M.
AU - van Loon, Karlijn
AU - Blanas, Athanasios
AU - Akbari, Parvin
AU - Roos, Arno
AU - Wong, Tse J.
AU - Denisov, Stepan S.
AU - Hackeng, Tilman M.
AU - Jimenez, Connie R.
AU - Nowak-Sliwinska, Patrycja
AU - Griffioen, Arjan W.
N1 - Funding Information: We are grateful to the following people for expert technical assistance and valuable discussions: Brenda Zaal, Willem van Dorp, Wietske Pieters, Alicia Veerman, Susanne Janssen, Matthijs van Kesteren, Aniek de Jong, Floor de Haan, Ida van der Peet, Sanne de Graaf, Roxanna Daghighian, Bram Priem, Zowi Huinen, Richard de Haas, Sander Piersma, Thang Pham, Maaike van Berkel, Haiko Karsjens, Aafke de Ligt, Meike de Wit, Jaco Knol, Beatriz Escudero Paniagua, Irene Bijnsdorp, Johan van Meerlo, Jan-David de Haan, Lisa Willemsen, Mathilda van Breest Smallenburg, Carla Molthof and Guus van Dongen (Amsterdam UMC), Sjoerd Klarenbeek, Kees Jalink, Ron Kerkhoven, Iris de Rink and Leila Nahidiazar (NKI Amsterdam), Diederik Engbersen (CimCure BV), Andrea Weiss (UNIGE, Geneva). Funding was obtained from Dutch Cancer Society KWF 2012-5480 (to J.R.v.B. and A.W.G.); EU H2020-SME INST-1-2015, Angio-Image (to A.W.G.); Health~Holland, PPP ALLOWANCE LSHM18007 (to A.W.G.); Dutch Cancer Society, KWF 2018–11651 (to A.W.G. and E.H.); Dutch Cancer Society, KWF 2020-13009 (to J.R.v.B.); European Research Council (ERC-680209 to PNS); Marie Curie Intra-European Fellowship for Career Development (PIEF-GA-2013-626797 to P.N.S.); Dutch Cancer Society KWF 2014-7234 (to P.N.S. and A.W.G.); EU, FP7-PEOPLE-2012-IEF, GENE, ID: 328695 (to E.H.); EU MSCA-IF-2019, #893910 (to P.A.); Cancer Center Amsterdam, Mass spectrometry infrastructure (to C.R.J.). Funding Information: We are grateful to the following people for expert technical assistance and valuable discussions: Brenda Zaal, Willem van Dorp, Wietske Pieters, Alicia Veerman, Susanne Janssen, Matthijs van Kesteren, Aniek de Jong, Floor de Haan, Ida van der Peet, Sanne de Graaf, Roxanna Daghighian, Bram Priem, Zowi Huinen, Richard de Haas, Sander Piersma, Thang Pham, Maaike van Berkel, Haiko Karsjens, Aafke de Ligt, Meike de Wit, Jaco Knol, Beatriz Escudero Paniagua, Irene Bijnsdorp, Johan van Meerlo, Jan-David de Haan, Lisa Willemsen, Mathilda van Breest Smallenburg, Carla Molthof and Guus van Dongen (Amsterdam UMC), Sjoerd Klarenbeek, Kees Jalink, Ron Kerkhoven, Iris de Rink and Leila Nahidiazar (NKI Amsterdam), Diederik Engbersen (CimCure BV), Andrea Weiss (UNIGE, Geneva). Funding was obtained from Dutch Cancer Society KWF 2012-5480 (to J.R.v.B. and A.W.G.); EU H2020-SME INST-1-2015, Angio-Image (to A.W.G.); Health~Holland, PPP ALLOWANCE LSHM18007 (to A.W.G.); Dutch Cancer Society, KWF 2018–11651 (to A.W.G. and E.H.); Dutch Cancer Society, KWF 2020-13009 (to J.R.v.B.); European Research Council (ERC-680209 to PNS); Marie Curie Intra-European Fellowship for Career Development (PIEF-GA-2013-626797 to P.N.S.); Dutch Cancer Society KWF 2014-7234 (to P.N.S. and A.W.G.); EU, FP7-PEOPLE-2012-IEF, GENE, ID: 328695 (to E.H.); EU MSCA-IF-2019, #893910 (to P.A.); Cancer Center Amsterdam, Mass spectrometry infrastructure (to C.R.J.). Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85130458817&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-022-30063-7
DO - https://doi.org/10.1038/s41467-022-30063-7
M3 - Article
C2 - 35606362
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2842
ER -