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  1. Article ; Online: Anti-angiogenic agents - overcoming tumour endothelial cell anergy and improving immunotherapy outcomes.

    Huinen, Zowi R / Huijbers, Elisabeth J M / van Beijnum, Judy R / Nowak-Sliwinska, Patrycja / Griffioen, Arjan W

    Nature reviews. Clinical oncology

    2021  Volume 18, Issue 8, Page(s) 527–540

    Abstract: Immune checkpoint inhibitors have revolutionized medical oncology, although currently only a subset of patients has a response to such treatment. A compelling body of evidence indicates that anti-angiogenic therapy has the capacity to ameliorate ... ...

    Abstract Immune checkpoint inhibitors have revolutionized medical oncology, although currently only a subset of patients has a response to such treatment. A compelling body of evidence indicates that anti-angiogenic therapy has the capacity to ameliorate antitumour immunity owing to the inhibition of various immunosuppressive features of angiogenesis. Hence, combinations of anti-angiogenic agents and immunotherapy are currently being tested in >90 clinical trials and 5 such combinations have been approved by the FDA in the past few years. In this Perspective, we describe how the angiogenesis-induced endothelial immune cell barrier hampers antitumour immunity and the role of endothelial cell anergy as the vascular counterpart of immune checkpoints. We review the antitumour immunity-promoting effects of anti-angiogenic agents and provide an update on the current clinical successes achieved when these agents are combined with immune checkpoint inhibitors. Finally, we propose that anti-angiogenic agents are immunotherapies - and vice versa - and discuss future research priorities.
    MeSH term(s) Angiogenesis Inhibitors/therapeutic use ; Animals ; Clonal Anergy/drug effects ; Combined Modality Therapy ; Drug Resistance, Neoplasm/immunology ; Humans ; Immunotherapy/methods ; Immunotherapy/trends ; Neoplasms/drug therapy ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Treatment Outcome ; Tumor Escape/drug effects ; Tumor Escape/physiology ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/immunology
    Chemical Substances Angiogenesis Inhibitors
    Language English
    Publishing date 2021-04-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2491410-1
    ISSN 1759-4782 ; 1759-4774
    ISSN (online) 1759-4782
    ISSN 1759-4774
    DOI 10.1038/s41571-021-00496-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6029: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)
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  2. Article ; Online: Pancreatic cancer-associated fibroblasts modulate macrophage differentiation via sialic acid-Siglec interactions.

    Boelaars, Kelly / Rodriguez, Ernesto / Huinen, Zowi R / Liu, Chang / Wang, Di / Springer, Babet O / Olesek, Katarzyna / Goossens-Kruijssen, Laura / van Ee, Thomas / Lindijer, Dimitri / Tak, Willemijn / de Haas, Aram / Wehry, Laetitia / Nugteren-Boogaard, Joline P / Mikula, Aleksandra / de Winde, Charlotte M / Mebius, Reina E / Tuveson, David A / Giovannetti, Elisa /
    Bijlsma, Maarten F / Wuhrer, Manfred / van Vliet, Sandra J / van Kooyk, Yvette

    Communications biology

    2024  Volume 7, Issue 1, Page(s) 430

    Abstract: Despite recent advances in cancer immunotherapy, pancreatic ductal adenocarcinoma (PDAC) remains unresponsive due to an immunosuppressive tumor microenvironment, which is characterized by the abundance of cancer-associated fibroblasts (CAFs). Once ... ...

    Abstract Despite recent advances in cancer immunotherapy, pancreatic ductal adenocarcinoma (PDAC) remains unresponsive due to an immunosuppressive tumor microenvironment, which is characterized by the abundance of cancer-associated fibroblasts (CAFs). Once identified, CAF-mediated immune inhibitory mechanisms could be exploited for cancer immunotherapy. Siglec receptors are increasingly recognized as immune checkpoints, and their ligands, sialic acids, are known to be overexpressed by cancer cells. Here, we unveil a previously unrecognized role of sialic acid-containing glycans on PDAC CAFs as crucial modulators of myeloid cells. Using multiplex immunohistochemistry and transcriptomics, we show that PDAC stroma is enriched in sialic acid-containing glycans compared to tumor cells and normal fibroblasts, and characterized by ST3GAL4 expression. We demonstrate that sialic acids on CAF cell lines serve as ligands for Siglec-7, -9, -10 and -15, distinct from the ligands on tumor cells, and that these receptors are found on myeloid cells in the stroma of PDAC biopsies. Furthermore, we show that CAFs drive the differentiation of monocytes to immunosuppressive tumor-associated macrophages in vitro, and that CAF sialylation plays a dominant role in this process compared to tumor cell sialylation. Collectively, our findings unravel sialic acids as a mechanism of CAF-mediated immunomodulation, which may provide targets for immunotherapy in PDAC.
    MeSH term(s) Humans ; Cancer-Associated Fibroblasts/metabolism ; N-Acetylneuraminic Acid/metabolism ; Sialic Acid Binding Immunoglobulin-like Lectins/metabolism ; Pancreatic Neoplasms/pathology ; Carcinoma, Pancreatic Ductal/metabolism ; Macrophages/metabolism ; Polysaccharides/metabolism ; Tumor Microenvironment
    Chemical Substances N-Acetylneuraminic Acid (GZP2782OP0) ; Sialic Acid Binding Immunoglobulin-like Lectins ; Polysaccharides
    Language English
    Publishing date 2024-04-09
    Publishing country England
    Document type Journal Article
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-024-06087-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: 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

    2022  Volume 26, Issue 2, Page(s) 279–293

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Humans ; Bevacizumab/immunology ; Bevacizumab/pharmacology ; Bevacizumab/therapeutic use ; Carcinoma, Renal Cell/drug therapy ; Carcinoma, Renal Cell/immunology ; Carcinoma, Renal Cell/pathology ; Endothelial Cells/drug effects ; Endothelial Cells/immunology ; Endothelial Cells/pathology ; Endothelium/drug effects ; Endothelium/immunology ; Endothelium/pathology ; Intercellular Adhesion Molecule-1/immunology ; Kidney Neoplasms/drug therapy ; Kidney Neoplasms/immunology ; Kidney Neoplasms/pathology ; Neovascularization, Pathologic/drug therapy ; Neovascularization, Pathologic/immunology ; Neovascularization, Pathologic/pathology ; Sunitinib/immunology ; Sunitinib/pharmacology ; Sunitinib/therapeutic use ; Vascular Endothelial Growth Factor A/immunology ; Immune Tolerance/drug effects ; Immune Tolerance/immunology ; Neoplasm Invasiveness/immunology ; Inflammation/drug therapy ; Inflammation/immunology ; Inflammation/pathology ; Angiogenesis Inhibitors/immunology ; Angiogenesis Inhibitors/pharmacology ; Angiogenesis Inhibitors/therapeutic use
    Chemical Substances Bevacizumab (2S9ZZM9Q9V) ; Intercellular Adhesion Molecule-1 (126547-89-5) ; Sunitinib (V99T50803M) ; Vascular Endothelial Growth Factor A ; Angiogenesis Inhibitors
    Language English
    Publishing date 2022-12-02
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1484717-6
    ISSN 1573-7209 ; 0969-6970
    ISSN (online) 1573-7209
    ISSN 0969-6970
    DOI 10.1007/s10456-022-09863-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5094: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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