1. Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response
- Author
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Carola Ries, Chia Huey Ooi, Kevin Kos, Seth B. Coffelt, Antoinette van Weverwijk, Kelly Kersten, Ji-Ying Song, Joachim L. Schultze, Jos Jonkers, Philippe A. Cassier, Camilla Salvagno, Karin E. de Visser, Sander Tuit, Metamia Ciampricotti, Dominik Rüttinger, Kim Vrijland, Thomas Ulas, and Cheei-Sing Hau
- Subjects
medicine.medical_treatment ,secondary [Mammary Neoplasms, Experimental] ,Mice ,0302 clinical medicine ,Interferon ,Antineoplastic Combined Chemotherapy Protocols ,Mice, Knockout ,drug effects [Macrophages] ,0303 health sciences ,physiology [Interferon Type I] ,Antibodies, Monoclonal ,Immunosuppression ,3. Good health ,Cell biology ,therapeutic use [Antineoplastic Combined Chemotherapy Protocols] ,030220 oncology & carcinogenesis ,Interferon Type I ,Female ,therapeutic use [Antibodies, Monoclonal] ,medicine.drug ,drug effects [Immunity, Innate] ,Mice, Transgenic ,Receptor, Macrophage Colony-Stimulating Factor ,Antibodies, Monoclonal, Humanized ,Article ,03 medical and health sciences ,Breast cancer ,therapeutic use [Cisplatin] ,Immunity ,ddc:570 ,Cell Line, Tumor ,medicine ,Animals ,Humans ,030304 developmental biology ,Cisplatin ,pathology [Mammary Neoplasms, Experimental] ,Chemotherapy ,drug therapy [Mammary Neoplasms, Experimental] ,business.industry ,Macrophages ,immunology [Mammary Neoplasms, Experimental] ,Mammary Neoplasms, Experimental ,Cancer ,Cell Biology ,medicine.disease ,Immunity, Innate ,Blockade ,Cancer research ,antagonists & inhibitors [Receptor, Macrophage Colony-Stimulating Factor] ,business ,emactuzumab - Abstract
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;Cdh1F/F;Trp53F/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.
- Published
- 2019
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