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 7

ALK1 affects the HPC niche in the BM.

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ALK1 affects the HPC niche in the BM. (A) Experimental design based on t...
(A) Experimental design based on the organ-on-a-chip assay with 3 channels. Representative images of a longitudinal and a cross section of the 3D tube are presented in the bottom panel. (B) Quantification of macrophage transendothelial migration at 24 and 48 hours with endothelial cells infected with lentiviral vectors expressing either scrambled or Acvrl1-targeting shRNA (n = 4 experiments). Data are represented as mean with SEM. *P < 0.05, unpaired, 2-tailed Student’s t test for the comparison between shCtrl and shA07 or shA09. (C–E) Experimental design of the short-term trial based on the orthotopic transplantation of 5 × 104 4T1 cells in syngeneic BALB/c hosts (tumor-free: n = 5 each for IgG2a and ALK1-Fc; neoadjuvant: n = 4 each for IgG2a and ALK1-Fc; adjuvant: n = 4 for IgG2a, n = 5 for ALK1-Fc) (C). Frequency of circulating Ly6ChiCD64– (D) and CD64+ (E) monocytes in peripheral blood. Data are represented as mean with SEM. (F) Frequency of Ly6C–CD64+ macrophages in lungs. Data are represented as mean with SEM. **P < 0.01, unpaired, 2-tailed Student’s t test. (G–I) FACS plot and gating strategy of c-Kit+Lin–Sca1– progenitor cells (47) extracted from the BM (G). Frequency of c-Kit+ (H) and GMP (I) cells from the BM extracts. Data are represented as mean with SEM. **P < 0.01, unpaired, 2-tailed Student’s t test. (J) Quantification of colony formation plating efficiency of c-Kit–enriched BM cells. Data are represented as mean with SEM. *P < 0.05, unpaired, 2-tailed Student’s t test. (K) Drawing summarizing the findings.