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An Activin Receptor-Like Kinase 1-governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases

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Title: An Activin Receptor-Like Kinase 1-governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases
Authors: Safaee Talkhoncheh, Mehrnaz, Sjölund, Jonas, Bolivar, Paulina, Kurzejamska, Ewa, Cordero, Eugenia, Vallès Pagès, Teia, Larsson, Sara, Lehn, Sophie, Frimannsson, Gustav, Ingesson, Viktor, Braun, Sebastian, Pantaleo, Jessica, Oudenaarden, Clara, Lauss, Martin, Pearsall, R Scott, Jönsson, Göran B, Rolny, Charlotte, Bocci, Matteo, Pietras, Kristian
Contributors: Lund University, Profile areas and other strong research environments, Other Strong Research Environments, LUCC: Lund University Cancer Centre, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Övriga starka forskningsmiljöer, LUCC: Lunds universitets cancercentrum, Originator, Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Translational Cancer Research, Experimental oncology, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för translationell cancerforskning, Experimentell onkologi, Originator, Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Translational Cancer Research, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för translationell cancerforskning, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section I, Melanoma, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion I, Melanom, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section I, Melanoma, Melanoma Genomics, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion I, Melanom, Melanoma Genomics, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section V, Surgery (Lund), Lund Melanoma Study Group, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion V, Kirurgi, Lund, Lunds Melanomstudiegrupp, Originator, Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Translational Cancer Research, Immuno-Oncology group, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för translationell cancerforskning, Immunonkologigruppen, Originator
Source: The Journal of clinical investigation. 135(5)
Subject Terms: Medical and Health Sciences, Clinical Medicine, Cancer and Oncology, Medicin och hälsovetenskap, Klinisk medicin, Cancer och onkologi
Description: The biology centered around the TGF-beta type I receptor Activin Receptor-Like Kinase (ALK)1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation. Notably, ACVRL1+ TAMs coincided with an immunosuppressive phenotype, and were over-represented in human cancers progressing on therapy. Accordingly, breast cancer patients with a prominent ACVRL1hi TAM signature exhibited a significantly shorter survival. In conclusion, we shed light on an unexpected multimodal regulation of tumorigenic phenotypes by ALK1 and demonstrate its utility as a target for anti-angiogenic immunotherapy.
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  Data: The biology centered around the TGF-beta type I receptor Activin Receptor-Like Kinase (ALK)1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation. Notably, ACVRL1+ TAMs coincided with an immunosuppressive phenotype, and were over-represented in human cancers progressing on therapy. Accordingly, breast cancer patients with a prominent ACVRL1hi TAM signature exhibited a significantly shorter survival. In conclusion, we shed light on an unexpected multimodal regulation of tumorigenic phenotypes by ALK1 and demonstrate its utility as a target for anti-angiogenic immunotherapy.
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