Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response

Recent studies have revealed a role for macrophages and neutrophils in limiting chemotherapy efficacy; however, the mechanisms underlying the therapeutic benefit of myeloid-targeting agents in combination with chemotherapy are incompletely understood. Here, we show that targeting tumour-associated m...

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Veröffentlicht in:	Nature cell biology Jg. 21; H. 4; S. 511 - 521
Hauptverfasser:	Salvagno, Camilla, Ciampricotti, Metamia, Tuit, Sander, Hau, Cheei-Sing, van Weverwijk, Antoinette, Coffelt, Seth B., Kersten, Kelly, Vrijland, Kim, Kos, Kevin, Ulas, Thomas, Song, Ji-Ying, Ooi, Chia-Huey, Rüttinger, Dominik, Cassier, Philippe A., Jonkers, Jos, Schultze, Joachim L., Ries, Carola H., de Visser, Karin E.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 01.04.2019 Nature Publishing Group
Schlagworte:	13/1 13/106 13/21 13/31 13/51 14/19 14/32 14/63 45/41 45/77 45/91 631/67 631/67/1059/99 631/67/327 631/67/580 64/110 64/60 82/79 Analysis Animals Antibodies, Monoclonal - therapeutic use Antibodies, Monoclonal, Humanized Anticancer properties Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biological response modifiers Biomedical and Life Sciences Breast cancer Cancer Cancer genetics Cancer patients Cancer Research Cancer therapies Cancer treatment Care and treatment Cell Biology Cell Line, Tumor Chemical compounds Chemotherapy Cisplatin Cisplatin - therapeutic use Colony-stimulating factor Cytotoxicity Developmental Biology Effectiveness Female Gene expression Genes Genetic engineering Humans Immune response Immunity Immunity, Innate - drug effects Immunogenicity Immunosuppression Immunosuppressive agents Immunotherapy Inflammation Interferon Interferon Type I - physiology Leukocytes (neutrophilic) Life Sciences Macrophage colony-stimulating factor Macrophages Macrophages - drug effects Mammary Neoplasms, Experimental - drug therapy Mammary Neoplasms, Experimental - immunology Mammary Neoplasms, Experimental - pathology Mammary Neoplasms, Experimental - secondary Mice Mice, Knockout Mice, Transgenic Neutrophils Pharmacology Platinum Receptor, Macrophage Colony-Stimulating Factor - antagonists & inhibitors Rodents Stem Cells Therapeutic targets Transgenic mice Treatment outcome Tumor microenvironment Tumors
ISSN:	1465-7392, 1476-4679, 1476-4679
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Zusammenfassung:	Recent studies have revealed a role for macrophages and neutrophils in limiting chemotherapy efficacy; however, the mechanisms underlying the therapeutic benefit of myeloid-targeting agents in combination with chemotherapy are incompletely understood. Here, we show that targeting tumour-associated macrophages by colony-stimulating factor-1 receptor (CSF-1R) blockade in the K14cre;Cdh1 F/F ;Trp53 F/F transgenic mouse model for breast cancer stimulates intratumoural type I interferon (IFN) signalling, which enhances the anticancer efficacy of platinum-based chemotherapeutics. Notably, anti-CSF-1R treatment also increased intratumoural expression of type I IFN-stimulated genes in patients with cancer, confirming that CSF-1R blockade is a powerful strategy to trigger an intratumoural type I IFN response. By inducing an inflamed, type I IFN-enriched tumour microenvironment and by further targeting immunosuppressive neutrophils during cisplatin therapy, antitumour immunity was activated in this poorly immunogenic breast cancer mouse model. These data illustrate the importance of breaching multiple layers of immunosuppression during cytotoxic therapy to successfully engage antitumour immunity in breast cancer. Salvagno et al. demonstrated that blocking tumour-associated macrophages in breast cancer enhances the efficacy of chemotherapeutics by promoting intratumoural type I interferon responses.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Current address: Molecular Pharmacology Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA Current address: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands Current address: Cancer Research UK Beatson Institute and Institute of Cancer Sciences, University of Glasgow, United Kingdom
ISSN:	1465-7392 1476-4679 1476-4679
DOI:	10.1038/s41556-019-0298-1