Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy.

Autor: Nowak-Sliwinska P; Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands. Patrycja.Nowak-Sliwinska@unige.ch.; School of Pharmaceutical Sciences, Faculty of Sciences, University of Geneva, Patrycja Nowak-Sliwinska, Rue Michel-Servet 1, CMU, 1211, Geneva 4, Switzerland. Patrycja.Nowak-Sliwinska@unige.ch.; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland. Patrycja.Nowak-Sliwinska@unige.ch., van Beijnum JR; Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.; CimCure BV, Amsterdam, The Netherlands., Griffioen CJ; Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands., Huinen ZR; Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands., Sopesens NG; Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands., Schulz R; Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands., Jenkins SV; Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA., Dings RPM; Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA., Groenendijk FH; Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands., Huijbers EJM; Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.; CimCure BV, Amsterdam, The Netherlands., Thijssen VLJL; Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands., Jonasch E; Department of Genitourinary Oncology, MD Anderson Cancer Center, Houston, TX, USA., Vyth-Dreese FA; Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Jordanova ES; Center for Gynaecologic Oncology Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands., Bex A; Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Division of Surgery and Interventional Science, Royal Free London NHS Foundation Trust, University College London, Pond Street, London, UK., Bernards R; Division of Molecular Carcinogenesis, Oncode Institute, Amsterdam, The Netherlands., de Gruijl TD; Immunotherapy Laboratory, Department of Medical Oncology, Amsterdam UMC, Cancer Center Amsterdam, Amsterdam, The Netherlands., Griffioen AW; Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands. a.griffioen@amsterdamumc.nl.; CimCure BV, Amsterdam, The Netherlands. a.griffioen@amsterdamumc.nl.
Jazyk: angličtina
Zdroj: Angiogenesis [Angiogenesis] 2023 May; Vol. 26 (2), pp. 279-293. Date of Electronic Publication: 2022 Dec 02.
DOI: 10.1007/s10456-022-09863-4
Abstrakt: Purpose: 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.
Experimental Design: 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.
Results: 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.
Conclusion: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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