{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T22:46:03Z","timestamp":1793400363003,"version":"4.5.0"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T00:00:00Z","timestamp":1669939200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T00:00:00Z","timestamp":1669939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"ERC","award":["EU-ERC680209"],"award-info":[{"award-number":["EU-ERC680209"]}]},{"name":"KWF","award":["VU2014-7234"],"award-info":[{"award-number":["VU2014-7234"]}]},{"name":"KWF","award":["VU2014-7234"],"award-info":[{"award-number":["VU2014-7234"]}]},{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["VU2012-5480"],"award-info":[{"award-number":["VU2012-5480"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["VU2012-5480"],"award-info":[{"award-number":["VU2012-5480"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P20GM103625"],"award-info":[{"award-number":["P20GM103625"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006389","name":"University of Geneva","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006389","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Angiogenesis"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Ongoing angiogenesis renders the tumor endothelium unresponsive to inflammatory cytokines and interferes with adhesion of leukocytes, resulting in escape from immunity. This process is referred to as tumor endothelial cell anergy. We aimed to investigate whether anti-angiogenic agents can overcome endothelial cell anergy and provide pro-inflammatory conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental design<\/jats:title>\n                    <jats:p>Tissues of renal cell carcinoma (RCC) patients treated with VEGF pathway-targeted drugs and control tissues were subject to RNAseq and immunohistochemical profiling of the leukocyte infiltrate. Analysis of adhesion molecule regulation in cultured endothelial cells, in a preclinical model and in human tissues was performed and correlated to leukocyte infiltration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>It is shown that treatment of RCC patients with the drugs sunitinib or bevacizumab overcomes tumor endothelial cell anergy. This treatment resulted in an augmented inflammatory state of the tumor, characterized by enhanced infiltration of all major leukocyte subsets, including T cells, regulatory T cells, macrophages of both M1- and M2-like phenotypes and activated dendritic cells. In vitro, exposure of angiogenic endothelial cells to anti-angiogenic drugs normalized ICAM-1 expression. In addition, a panel of tyrosine kinase inhibitors was shown to increase transendothelial migration of both non-adherent and monocytic leukocytes. In primary tumors of RCC patients, ICAM-1 expression was found to be significantly increased in both the sunitinib and bevacizumab-treated groups. Genomic analysis confirmed the correlation between increased immune cell infiltration and ICAM-1 expression upon VEGF-targeted treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The results support the emerging concept that anti-angiogenic therapy can boost immunity and show how immunotherapy approaches can benefit from combination with anti-angiogenic compounds.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10456-022-09863-4","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T03:29:45Z","timestamp":1669951785000},"page":"279-293","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy"],"prefix":"10.1007","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8299-0444","authenticated-orcid":false,"given":"Patrycja","family":"Nowak-Sliwinska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy R.","family":"van Beijnum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian J.","family":"Griffioen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zowi R.","family":"Huinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine Grima","family":"Sopesens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Schulz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir V.","family":"Jenkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruud P. M.","family":"Dings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floris H.","family":"Groenendijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth J. M.","family":"Huijbers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor L. J. L.","family":"Thijssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Jonasch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florry A.","family":"Vyth-Dreese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina S.","family":"Jordanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Bex","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"Bernards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja D.","family":"de Gruijl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8508-4754","authenticated-orcid":false,"given":"Arjan W.","family":"Griffioen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,12,2]]},"reference":[{"issue":"2","key":"9863_CR1","first-page":"237","volume":"52","author":"AW Griffioen","year":"2000","unstructured":"Griffioen AW, Molema G (2000) Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 52(2):237\u2013268","journal-title":"Pharmacol Rev"},{"issue":"5","key":"9863_CR2","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","volume":"144","author":"D Hanahan","year":"2011","unstructured":"Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646\u2013674","journal-title":"Cell"},{"issue":"8","key":"9863_CR3","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/s41571-021-00496-y","volume":"18","author":"Z Huinen","year":"2021","unstructured":"Huinen Z, Huijbers EJM, Van Beijnum JR, Nowak-Sliwinska P, Griffioen AW (2021) Anti-angiogenic agents - overcoming tumor endothelial cell anergy and improving immunotherapy outcomes. Nat Rev Clin Oncol 18(8):527\u2013540","journal-title":"Nat Rev Clin Oncol"},{"issue":"12","key":"9863_CR4","doi-asserted-by":"publisher","first-page":"4878","DOI":"10.1182\/blood-2002-07-1956","volume":"101","author":"JE Ohm","year":"2003","unstructured":"Ohm JE, Gabrilovich DI, Sempowski GD, Kisseleva E, Parman KS, Nadaf S, Carbone DP (2003) VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 101(12):4878\u20134886","journal-title":"Blood"},{"issue":"1","key":"9863_CR5","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1096\/fj.14-250985","volume":"29","author":"H Huang","year":"2015","unstructured":"Huang H, Langenkamp E, Georganaki M, Loskog A, Fuchs PF, Dieterich LC, Kreuger J, Dimberg A (2015) VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-kappaB-induced endothelial activation. FASEB J 29(1):227\u2013238","journal-title":"FASEB J"},{"issue":"2","key":"9863_CR6","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1084\/jem.20140559","volume":"212","author":"T Voron","year":"2015","unstructured":"Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, Latreche S, Bergaya S, Benhamouda N, Tanchot C et al (2015) VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med 212(2):139\u2013148","journal-title":"J Exp Med"},{"issue":"3","key":"9863_CR7","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1159\/000505695","volume":"9","author":"H Deng","year":"2020","unstructured":"Deng H, Kan A, Lyu N, Mu L, Han Y, Liu L, Zhang Y, Duan Y, Liao S, Li S et al (2020) Dual vascular endothelial growth factor receptor and fibroblast growth factor receptor inhibition elicits antitumor immunity and enhances programmed cell death-1 checkpoint blockade in hepatocellular carcinoma. Liver Cancer 9(3):338\u2013357","journal-title":"Liver Cancer"},{"issue":"10","key":"9863_CR8","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1038\/nm1096-1096","volume":"2","author":"DI Gabrilovich","year":"1996","unstructured":"Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2(10):1096\u20131103","journal-title":"Nat Med"},{"issue":"1","key":"9863_CR9","doi-asserted-by":"publisher","first-page":"4064","DOI":"10.1038\/s41467-020-17914-x","volume":"11","author":"JH Im","year":"2020","unstructured":"Im JH, Buzzelli JN, Jones K, Franchini F, Gordon-Weeks A, Markelc B, Chen J, Kim J, Cao Y, Muschel RJ (2020) FGF2 alters macrophage polarization, tumour immunity and growth and can be targeted during radiotherapy. Nat Commun 11(1):4064","journal-title":"Nat Commun"},{"issue":"3","key":"9863_CR10","first-page":"881","volume":"29","author":"J Wada","year":"2009","unstructured":"Wada J, Suzuki H, Fuchino R, Yamasaki A, Nagai S, Yanai K, Koga K, Nakamura M, Tanaka M, Morisaki T et al (2009) The contribution of vascular endothelial growth factor to the induction of regulatory T-cells in malignant effusions. Anticancer Res 29(3):881\u2013888","journal-title":"Anticancer Res"},{"issue":"2","key":"9863_CR11","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1182\/blood-2007-01-065714","volume":"110","author":"Y Huang","year":"2007","unstructured":"Huang Y, Chen X, Dikov MM, Novitskiy SV, Mosse CA, Yang L, Carbone DP (2007) Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood 110(2):624\u2013631","journal-title":"Blood"},{"issue":"3","key":"9863_CR12","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1007\/s10549-013-2829-y","volume":"143","author":"T Ye","year":"2014","unstructured":"Ye T, Wei X, Yin T, Xia Y, Li D, Shao B, Song X, He S, Luo M, Gao X et al (2014) Inhibition of FGFR signaling by PD173074 improves antitumor immunity and impairs breast cancer metastasis. Breast Cancer Res Treat 143(3):435\u2013446","journal-title":"Breast Cancer Res Treat"},{"issue":"5","key":"9863_CR13","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1200\/JCO.2005.06.081","volume":"23","author":"DJ Hicklin","year":"2005","unstructured":"Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23(5):1011\u20131027","journal-title":"J Clin Oncol"},{"key":"9863_CR14","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.canlet.2020.05.015","volume":"487","author":"L Schito","year":"2020","unstructured":"Schito L, Rey S (2020) Hypoxia: turning vessels into vassals of cancer immunotolerance. Cancer Lett 487:74\u201384","journal-title":"Cancer Lett"},{"issue":"2","key":"9863_CR15","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1182\/blood.V88.2.667.bloodjournal882667","volume":"88","author":"AW Griffioen","year":"1996","unstructured":"Griffioen AW, Damen CA, Blijham GH, Groenewegen G (1996) Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood 88(2):667\u2013673","journal-title":"Blood"},{"issue":"5","key":"9863_CR16","first-page":"1111","volume":"56","author":"AW Griffioen","year":"1996","unstructured":"Griffioen AW, Damen CA, Martinotti S, Blijham GH, Groenewegen G (1996) Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors. Cancer Res 56(5):1111\u20131117","journal-title":"Cancer Res"},{"issue":"9","key":"9863_CR17","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1038\/nm0996-992","volume":"2","author":"RJ Melder","year":"1996","unstructured":"Melder RJ, Koenig GC, Witwer BP, Safabakhsh N, Munn LL, Jain RK (1996) During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat Med 2(9):992\u2013997","journal-title":"Nat Med"},{"issue":"9","key":"9863_CR18","first-page":"2322","volume":"63","author":"AE Dirkx","year":"2003","unstructured":"Dirkx AE, Oude Egbrink MG, Kuijpers MJ, van der Niet ST, Heijnen VV, Bouma-ter Steege JC, Wagstaff J, Griffioen AW (2003) Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression. Cancer Res 63(9):2322\u20132329","journal-title":"Cancer Res"},{"key":"9863_CR19","doi-asserted-by":"publisher","first-page":"367","DOI":"10.3389\/fonc.2018.00367","volume":"8","author":"D Klein","year":"2018","unstructured":"Klein D (2018) The tumor vascular endothelium as decision maker in cancer therapy. Front Oncol 8:367","journal-title":"Front Oncol"},{"key":"9863_CR20","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.smim.2018.02.002","volume":"35","author":"F De Sanctis","year":"2018","unstructured":"De Sanctis F, Ugel S, Facciponte J, Facciabene A (2018) The dark side of tumor-associated endothelial cells. Semin Immunol 35:35\u201347","journal-title":"Semin Immunol"},{"key":"9863_CR21","doi-asserted-by":"publisher","first-page":"eabm6388","DOI":"10.1126\/sciimmunol.abm6388","volume":"7","author":"EJ Huijbers","year":"2022","unstructured":"Huijbers EJ, Khan KA, Kerbel RS, Griffioen AW (2022) Tumors resurrect an embryonic vascular gene program to escape immunity. Sci Immunol 7:eabm6388","journal-title":"Sci Immunol"},{"issue":"20","key":"9863_CR22","doi-asserted-by":"publisher","first-page":"6674","DOI":"10.1158\/1078-0432.CCR-07-5212","volume":"14","author":"JH Finke","year":"2008","unstructured":"Finke JH, Rini B, Ireland J, Rayman P, Richmond A, Golshayan A, Wood L, Elson P, Garcia J, Dreicer R et al (2008) Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res 14(20):6674\u20136682","journal-title":"Clin Cancer Res"},{"issue":"6","key":"9863_CR23","doi-asserted-by":"publisher","first-page":"2148","DOI":"10.1158\/1078-0432.CCR-08-1332","volume":"15","author":"JS Ko","year":"2009","unstructured":"Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J et al (2009) Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15(6):2148\u20132157","journal-title":"Clin Cancer Res"},{"issue":"10","key":"9863_CR24","first-page":"2963","volume":"5","author":"DI Gabrilovich","year":"1999","unstructured":"Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP (1999) Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res 5(10):2963\u20132970","journal-title":"Clin Cancer Res"},{"issue":"10","key":"9863_CR25","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1007\/s00262-015-1735-z","volume":"64","author":"A Guislain","year":"2015","unstructured":"Guislain A, Gadiot J, Kaiser A, Jordanova ES, Broeks A, Sanders J, van Boven H, de Gruijl TD, Haanen JB, Bex A et al (2015) Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma. Cancer Immunol Immunother 64(10):1241\u20131250","journal-title":"Cancer Immunol Immunother"},{"issue":"5706","key":"9863_CR26","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1126\/science.1104819","volume":"307","author":"RK Jain","year":"2005","unstructured":"Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58\u201362","journal-title":"Science"},{"issue":"11","key":"9863_CR27","doi-asserted-by":"publisher","first-page":"3395","DOI":"10.1158\/1078-0432.CCR-06-2441","volume":"13","author":"RP Dings","year":"2007","unstructured":"Dings RP, Loren M, Heun H, McNiel E, Griffioen AW, Mayo KH, Griffin RJ (2007) Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization. Clin Cancer Res 13(11):3395\u20133402","journal-title":"Clin Cancer Res"},{"key":"9863_CR28","doi-asserted-by":"publisher","first-page":"8990","DOI":"10.1038\/srep08990","volume":"5","author":"A Weiss","year":"2015","unstructured":"Weiss A, Bonvin D, Berndsen RH, Scherrer E, Wong TJ, Dyson PJ, Griffioen AW, Nowak-Sliwinska P (2015) Angiostatic treatment prior to chemo- or photodynamic therapy improves anti-tumor efficacy. Sci Rep 5:8990","journal-title":"Sci Rep"},{"issue":"10","key":"9863_CR29","doi-asserted-by":"publisher","first-page":"3134","DOI":"10.1158\/1078-0432.CCR-10-2443","volume":"17","author":"RP Dings","year":"2011","unstructured":"Dings RP, Vang KB, Castermans K, Popescu F, Zhang Y, Oude Egbrink MG, Mescher MF, Farrar MA, Griffioen AW, Mayo KH (2011) Enhancement of T-cell-mediated antitumor response: angiostatic adjuvant to immunotherapy against cancer. Clin Cancer Res 17(10):3134\u20133145","journal-title":"Clin Cancer Res"},{"issue":"1","key":"9863_CR30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.immuni.2013.07.012","volume":"39","author":"DS Chen","year":"2013","unstructured":"Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1):1\u201310","journal-title":"Immunity"},{"issue":"5795","key":"9863_CR31","doi-asserted-by":"publisher","first-page":"1960","DOI":"10.1126\/science.1129139","volume":"313","author":"J Galon","year":"2006","unstructured":"Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960\u20131964","journal-title":"Science"},{"issue":"7528","key":"9863_CR32","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/nature14011","volume":"515","author":"RS Herbst","year":"2014","unstructured":"Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563\u2013567","journal-title":"Nature"},{"issue":"24","key":"9863_CR33","doi-asserted-by":"publisher","first-page":"2288","DOI":"10.1056\/NEJMoa1716948","volume":"378","author":"MA Socinski","year":"2018","unstructured":"Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodriguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F et al (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378(24):2288\u20132301","journal-title":"N Engl J Med"},{"issue":"12","key":"9863_CR34","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1056\/NEJMoa1816047","volume":"380","author":"RJ Motzer","year":"2019","unstructured":"Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M et al (2019) Avelumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N Engl J Med 380(12):1103\u20131115","journal-title":"N Engl J Med"},{"issue":"4","key":"9863_CR35","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1016\/j.urology.2011.05.034","volume":"78","author":"A Bex","year":"2011","unstructured":"Bex A, Blank C, Meinhardt W, van Tinteren H, Horenblas S, Haanen J (2011) A phase II study of Presurgical Sunitinib in patients with metastatic clear-cell renal carcinoma and the primary tumor in situ. Urology 78(4):832\u2013837","journal-title":"Urology"},{"issue":"3","key":"9863_CR36","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.eururo.2011.05.028","volume":"60","author":"T Powles","year":"2011","unstructured":"Powles T, Blank C, Chowdhury S, Horenblas S, Peters J, Shamash J, Sarwar N, Boleti E, Sahdev A, O\u2019Brien T et al (2011) The outcome of patients treated with sunitinib prior to planned nephrectomy in metastatic clear cell renal cancer. Eur Urol 60(3):448\u2013454","journal-title":"Eur Urol"},{"issue":"25","key":"9863_CR37","doi-asserted-by":"publisher","first-page":"4076","DOI":"10.1200\/JCO.2008.21.3660","volume":"27","author":"E Jonasch","year":"2009","unstructured":"Jonasch E, Wood CG, Matin SF, Tu SM, Pagliaro LC, Corn PG, Aparicio A, Tamboli P, Millikan RE, Wang X et al (2009) Phase II presurgical feasibility study of bevacizumab in untreated patients with metastatic renal cell carcinoma. J Clin Oncol 27(25):4076\u20134081","journal-title":"J Clin Oncol"},{"issue":"3","key":"9863_CR38","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1007\/s10456-018-9613-x","volume":"21","author":"P Nowak-Sliwinska","year":"2018","unstructured":"Nowak-Sliwinska P, Alitalo K, Allen E, Anisimov A, Aplin AC, Auerbach R, Augustin HG, Bates DO, van Beijnum JR, Bender RHF et al (2018) Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis 21(3):425\u2013532","journal-title":"Angiogenesis"},{"issue":"14","key":"9863_CR39","doi-asserted-by":"publisher","first-page":"3961","DOI":"10.1158\/1078-0432.CCR-12-0002","volume":"18","author":"AW Griffioen","year":"2012","unstructured":"Griffioen AW, Mans LA, de Graaf AMA, Nowak-Sliwinska P, de Hoog C, de Jong TAM, Vyth-Dreese FA, van Beijnum JR, Bex A, Jonasch E (2012) Rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients. Clin Cancer Res 18(14):3961\u20133971","journal-title":"Clin Cancer Res"},{"issue":"2","key":"9863_CR40","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.yexcr.2004.06.014","volume":"299","author":"VL Thijssen","year":"2004","unstructured":"Thijssen VL, Brandwijk RJ, Dings RP, Griffioen AW (2004) Angiogenesis gene expression profiling in xenograft models to study cellular interactions. Exp Cell Res 299(2):286\u2013293","journal-title":"Exp Cell Res"},{"issue":"5","key":"9863_CR41","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nmeth.3337","volume":"12","author":"AM Newman","year":"2015","unstructured":"Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA (2015) Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 12(5):453\u2013457","journal-title":"Nat Methods"},{"issue":"8","key":"9863_CR42","doi-asserted-by":"publisher","first-page":"2431","DOI":"10.1158\/1078-0432.CCR-07-4089","volume":"14","author":"AA van der Veldt","year":"2008","unstructured":"van der Veldt AA, Meijerink MR, van den Eertwegh AJ, Bex A, de Gast G, Haanen JB, Boven E (2008) Sunitinib for treatment of advanced renal cell cancer: primary tumor response. Clin Cancer Res 14(8):2431\u20132436","journal-title":"Clin Cancer Res"},{"key":"9863_CR43","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41467-022-30063-7","volume":"13","author":"JR Van Beijnum","year":"2022","unstructured":"Van Beijnum JR, Huijbers EJM, Van Loon K, Blanas A, Akbari P, Roos A, Wong TJ, Denisov S, Jimenez CR, Hackeng TM et al (2022) Extracellular vimentin mimics VEGF and is a target for anti-angiogenic immunotherapy. Nat Commun 13:20","journal-title":"Nat Commun"},{"issue":"10","key":"9863_CR44","doi-asserted-by":"publisher","first-page":"3086","DOI":"10.1002\/(SICI)1521-4141(199810)28:10<3086::AID-IMMU3086>3.0.CO;2-Z","volume":"28","author":"Y Reiss","year":"1998","unstructured":"Reiss Y, Hoch G, Deutsch U, Engelhardt B (1998) T cell interaction with ICAM-1-deficient endothelium in vitro: essential role for ICAM-1 and ICAM-2 in transendothelial migration of T cells. Eur J Immunol 28(10):3086\u20133099","journal-title":"Eur J Immunol"},{"issue":"9","key":"9863_CR45","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1158\/2326-6066.CIR-14-0244","volume":"3","author":"XD Liu","year":"2015","unstructured":"Liu XD, Hoang A, Zhou L, Kalra S, Yetil A, Sun M, Ding Z, Zhang X, Bai S, German P et al (2015) Resistance to antiangiogenic therapy is associated with an immunosuppressive tumor microenvironment in metastatic renal cell carcinoma. Cancer Immunol Res 3(9):1017\u20131029","journal-title":"Cancer Immunol Res"},{"issue":"11","key":"9863_CR46","first-page":"692","volume":"15","author":"D Vestweber","year":"2015","unstructured":"Vestweber D (2015) How leukocytes cross the vascular endothelium. Nat Rev 15(11):692\u2013704","journal-title":"Nat Rev"},{"issue":"5","key":"9863_CR47","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/nrclinonc.2018.9","volume":"15","author":"KA Khan","year":"2018","unstructured":"Khan KA, Kerbel RS (2018) Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol 15(5):310\u2013324","journal-title":"Nat Rev Clin Oncol"},{"issue":"12","key":"9863_CR48","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1056\/NEJMoa1816714","volume":"380","author":"BI Rini","year":"2019","unstructured":"Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulieres D, Melichar B et al (2019) Pembrolizumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N Engl J Med 380(12):1116\u20131127","journal-title":"N Engl J Med"},{"issue":"20","key":"9863_CR49","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1056\/NEJMoa1915745","volume":"382","author":"RS Finn","year":"2020","unstructured":"Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO et al (2020) Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382(20):1894\u20131905","journal-title":"N Engl J Med"},{"issue":"2","key":"9863_CR50","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1124\/pr.114.010215","volume":"67","author":"JR van Beijnum","year":"2015","unstructured":"van Beijnum JR, Nowak-Sliwinska P, Huijbers EJ, Thijssen VL, Griffioen AW (2015) The great escape; the hallmarks of resistance to antiangiogenic therapy. Pharmacol Rev 67(2):441\u2013461","journal-title":"Pharmacol Rev"},{"issue":"1","key":"9863_CR51","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/s10456-019-09698-6","volume":"23","author":"EA Kuczynski","year":"2020","unstructured":"Kuczynski EA, Reynolds AR (2020) Vessel co-option and resistance to anti-angiogenic therapy. Angiogenesis 23(1):55\u201374","journal-title":"Angiogenesis"},{"issue":"1","key":"9863_CR52","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s10456-019-09684-y","volume":"23","author":"Y Zhang","year":"2020","unstructured":"Zhang Y, Wang S, Dudley AC (2020) Models and molecular mechanisms of blood vessel co-option by cancer cells. Angiogenesis 23(1):17\u201325","journal-title":"Angiogenesis"},{"issue":"6","key":"9863_CR53","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1096\/fj.05-4493com","volume":"20","author":"AE Dirkx","year":"2006","unstructured":"Dirkx AE, oude Egbrink MG, Castermans K, van der Schaft DW, Thijssen VL, Dings RP, Kwee L, Mayo KH, Wagstaff J, Bouma-ter Steege JC et al (2006) Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors. Faseb J 20(6):621\u2013630","journal-title":"Faseb J"},{"issue":"6","key":"9863_CR54","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1007\/s00262-015-1678-4","volume":"64","author":"S Punt","year":"2015","unstructured":"Punt S, van Vliet ME, Spaans VM, de Kroon CD, Fleuren GJ, Gorter A, Jordanova ES (2015) FoxP3(+) and IL-17(+) cells are correlated with improved prognosis in cervical adenocarcinoma. Cancer Immunol Immunother 64(6):745\u2013753","journal-title":"Cancer Immunol Immunother"},{"issue":"1","key":"9863_CR55","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s40425-019-0497-0","volume":"7","author":"SJ Santegoets","year":"2019","unstructured":"Santegoets SJ, Duurland CL, Jordanova ES, van Ham JJ, Ehsan I, van Egmond SL, Welters MJP, van der Burg SH (2019) Tbet-positive regulatory T cells accumulate in oropharyngeal cancers with ongoing tumor-specific type 1 T cell responses. J Immunother Cancer 7(1):14","journal-title":"J Immunother Cancer"},{"issue":"4","key":"9863_CR56","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1177\/039463200601900406","volume":"19","author":"V Flati","year":"2006","unstructured":"Flati V, Pastore LI, Griffioen AW, Satijn S, Toniato E, D\u2019Alimonte I, Laglia E, Marchetti P, Gulino A, Martinotti S (2006) Endothelial cell anergy is mediated by bFGF through the sustained activation of p38-MAPK and NF-eb inhibition. Int J Immunopathol Pharmacol 19(4):761\u2013773","journal-title":"Int J Immunopathol Pharmacol"},{"issue":"22","key":"9863_CR57","doi-asserted-by":"publisher","first-page":"10770","DOI":"10.1158\/0008-5472.CAN-06-1609","volume":"66","author":"DM Hellebrekers","year":"2006","unstructured":"Hellebrekers DM, Castermans K, Vire E, Dings RP, Hoebers NT, Mayo KH, Oude Egbrink MG, Molema G, Fuks F, van Engeland M et al (2006) Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications. Cancer Res 66(22):10770\u201310777","journal-title":"Cancer Res"},{"issue":"4","key":"9863_CR58","doi-asserted-by":"publisher","first-page":"477","DOI":"10.21873\/cgp.20334","volume":"19","author":"AM Ferician","year":"2022","unstructured":"Ferician AM, Ferician OC, Cumpanas AD, Berzava PL, Nesiu A, Barmayoun A, Cimpean AM (2022) Heterogeneity of platelet derived growth factor pathway gene expression profile defines three distinct subgroups of renal cell carcinomas. Cancer Genom Proteom 19(4):477\u2013489","journal-title":"Cancer Genom Proteom"},{"issue":"1","key":"9863_CR59","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s10020-019-0114-1","volume":"25","author":"WH Chang","year":"2019","unstructured":"Chang WH, Lai AG (2019) An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components. Mol Med 25(1):46","journal-title":"Mol Med"},{"issue":"7637","key":"9863_CR60","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/nature21349","volume":"541","author":"DS Chen","year":"2017","unstructured":"Chen DS, Mellman I (2017) Elements of cancer immunity and the cancer-immune set point. Nature 541(7637):321\u2013330","journal-title":"Nature"}],"container-title":["Angiogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10456-022-09863-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10456-022-09863-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10456-022-09863-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T06:48:31Z","timestamp":1681973311000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10456-022-09863-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,2]]},"references-count":60,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,5]]}},"alternative-id":["9863"],"URL":"https:\/\/doi.org\/10.1007\/s10456-022-09863-4","relation":{},"ISSN":["0969-6970","1573-7209"],"issn-type":[{"value":"0969-6970","type":"print"},{"value":"1573-7209","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,2]]},"assertion":[{"value":"10 August 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 November 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors have no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}