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

Patrycja Nowak-Sliwinska*, Judy R. van Beijnum, Christian J. Griffioen, Zowi R. Huinen, Nadine Grima Sopesens, Ralph Schulz, Samir V. Jenkins, Ruud P.M. Dings, Floris H. Groenendijk, Elisabeth J.M. Huijbers, Victor L.J.L. Thijssen, Eric Jonasch, Florry A. Vyth-Dreese, Ekaterina S. Jordanova, Axel Bex, René Bernards, Tanja D. de Gruijl, Arjan W. Griffioen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Number of pages15
Publication statusE-pub ahead of print - 2 Dec 2022

Bibliographical note

Funding Information:
The current study was performed with support from the Dutch Cancer Society ‘Het Koningin Wilhelmina Fonds’ (VU2012-5480 to JRvB and AWG and VU2014-7234 to AWG and PNS), the European Research Council (EU-ERC680209 Starting Grant, to PNS) and the National Institute of Health (P20GM103625 to RPMD).

Publisher Copyright: © 2022, The Author(s).


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