An activin receptor-like kinase 1–governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases
Mehrnaz Safaee Talkhoncheh, Jonas Sjölund, Paulina Bolivar, Ewa Kurzejamska, Eugenia Cordero, Teia Vallès Pagès, Sara Larsson, Sophie Lehn, Gustav Frimannsson, Viktor Ingesson, Sebastian Braun, Jessica Pantaleo, Clara Oudenaarden, Martin Lauss, R. Scott Pearsall, Göran Jönsson, Charlotte Rolny, Matteo Bocci, Kristian Pietras
Mehrnaz Safaee Talkhoncheh, Jonas Sjölund, Paulina Bolivar, Ewa Kurzejamska, Eugenia Cordero, Teia Vallès Pagès, Sara Larsson, Sophie Lehn, Gustav Frimannsson, Viktor Ingesson, Sebastian Braun, Jessica Pantaleo, Clara Oudenaarden, Martin Lauss, R. Scott Pearsall, Göran Jönsson, Charlotte Rolny, Matteo Bocci, Kristian Pietras
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Research Article Immunology Oncology

An activin receptor-like kinase 1–governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases

Abstract

The biology centered around the TGF-β 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 2 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 antiangiogenic 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 overrepresented 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 antiangiogenic immunotherapy.

Authors

Mehrnaz Safaee Talkhoncheh, Jonas Sjölund, Paulina Bolivar, Ewa Kurzejamska, Eugenia Cordero, Teia Vallès Pagès, Sara Larsson, Sophie Lehn, Gustav Frimannsson, Viktor Ingesson, Sebastian Braun, Jessica Pantaleo, Clara Oudenaarden, Martin Lauss, R. Scott Pearsall, Göran Jönsson, Charlotte Rolny, Matteo Bocci, Kristian Pietras

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Figure 2

Murine and human macrophages express Acvrl1/ACVRL1.

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Murine and human macrophages express Acvrl1/ACVRL1. (A and B) Study desi...
(A and B) Study design (A) for the quantification of Acvrl1 expression in FACS-sorted immune cell populations from the MMTV-PyMT model (3 pooled experiments) (B). Positive (CD31+ endothelial cells) and negative (EpCAM+ epithelial cells) controls highlighted in magenta and purple, respectively. Expression of ACVRL1 in freshly isolated human CD14+ monocytes from healthy donors (green). Data are represented as mean with SEM. (C) Expression of Id1 in unstimulated (control) versus BMP9-stimulated BM-derived macrophages (representative of 3 independent experiments). Data are represented as mean with SEM. ***P < 0.001, unpaired, 2-tailed Student’s t test. (D) Overlay of a TAM-specific ACVRL1 signature onto myeloid cells of a human breast cancer scRNA-Seq dataset (32). (E) Expression of ACVRL1 in TAMs from the scRNA-Seq atlas of immune phenotypes (29, 30). Density plot of the expression of ACVRL1 in TAMs. The average expression of the genes composing the TAM signature is presented in the heatmap for ACVRL1+ and ACVRL1– TAM populations. (F) Heatmap of the expression of ACVRL1, cluster markers, and prototypical TAM markers in the scRNA-Seq atlas of immune phenotypes (29). (G) Dual RNAscope ISH coupled with mIHC in human breast cancer. The protein markers CD31 (magenta) and CD45 (white) were used to describe the cellular distribution of the ACVRL1 probe (green). Scale bars: 20 μm; 10 μm (inlet). Two inlets were annotated to highlight endothelial (cyan inlet/arrows) or immune-restricted accumulation of ACVRL1 (yellow inlets/arrows).