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Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy
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 o...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Netherlands
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10119234/ https://www.ncbi.nlm.nih.gov/pubmed/36459240 http://dx.doi.org/10.1007/s10456-022-09863-4 |
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author | Nowak-Sliwinska, Patrycja van Beijnum, Judy R. Griffioen, Christian J. Huinen, Zowi R. Sopesens, Nadine Grima Schulz, Ralph Jenkins, Samir V. Dings, Ruud P. M. Groenendijk, Floris H. Huijbers, Elisabeth J. M. Thijssen, Victor L. J. L. Jonasch, Eric Vyth-Dreese, Florry A. Jordanova, Ekaterina S. Bex, Axel Bernards, René de Gruijl, Tanja D. Griffioen, Arjan W. |
author_facet | Nowak-Sliwinska, Patrycja van Beijnum, Judy R. Griffioen, Christian J. Huinen, Zowi R. Sopesens, Nadine Grima Schulz, Ralph Jenkins, Samir V. Dings, Ruud P. M. Groenendijk, Floris H. Huijbers, Elisabeth J. M. Thijssen, Victor L. J. L. Jonasch, Eric Vyth-Dreese, Florry A. Jordanova, Ekaterina S. Bex, Axel Bernards, René de Gruijl, Tanja D. Griffioen, Arjan W. |
author_sort | Nowak-Sliwinska, Patrycja |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version of this article contains supplementary available 10.1007/s10456-022-09863-4. |
format | Online Article Text |
id | pubmed-10119234 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer Netherlands |
record_format | MEDLINE/PubMed |
spelling | pubmed-101192342023-04-22 Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy Nowak-Sliwinska, Patrycja van Beijnum, Judy R. Griffioen, Christian J. Huinen, Zowi R. Sopesens, Nadine Grima Schulz, Ralph Jenkins, Samir V. Dings, Ruud P. M. Groenendijk, Floris H. Huijbers, Elisabeth J. M. Thijssen, Victor L. J. L. Jonasch, Eric Vyth-Dreese, Florry A. Jordanova, Ekaterina S. Bex, Axel Bernards, René de Gruijl, Tanja D. Griffioen, Arjan W. Angiogenesis Original Paper 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. SUPPLEMENTARY INFORMATION: The online version of this article contains supplementary available 10.1007/s10456-022-09863-4. Springer Netherlands 2022-12-02 2023 /pmc/articles/PMC10119234/ /pubmed/36459240 http://dx.doi.org/10.1007/s10456-022-09863-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Paper Nowak-Sliwinska, Patrycja van Beijnum, Judy R. Griffioen, Christian J. Huinen, Zowi R. Sopesens, Nadine Grima Schulz, Ralph Jenkins, Samir V. Dings, Ruud P. M. Groenendijk, Floris H. Huijbers, Elisabeth J. M. Thijssen, Victor L. J. L. Jonasch, Eric Vyth-Dreese, Florry A. Jordanova, Ekaterina S. Bex, Axel Bernards, René de Gruijl, Tanja D. Griffioen, Arjan W. Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy |
title | Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy |
title_full | Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy |
title_fullStr | Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy |
title_full_unstemmed | Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy |
title_short | Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy |
title_sort | proinflammatory activity of vegf-targeted treatment through reversal of tumor endothelial cell anergy |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10119234/ https://www.ncbi.nlm.nih.gov/pubmed/36459240 http://dx.doi.org/10.1007/s10456-022-09863-4 |
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