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 5

Antiangiogenic IT elicits tumor-specific and systemic effects on the immune cell composition.

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Antiangiogenic IT elicits tumor-specific and systemic effects on the imm...
(A) Experimental design of the 4T1-based adjuvant trial to study different population of myeloid and lymphoid cells via FACS. (B) Representative FACS plots for the myeloid compartment in the different cohorts (n = 5 each for IgG2a and ALK1-Fc, n = 6 each for IT and ALK1-Fc + IT). (C and D) From the CD11b+ gating, relative abundance of monocytes in lung tissue: Ly6ChiCD64– (C), and Ly6ChiCD64+ (D). Data are represented as mean with SEM. P value: unpaired, 2-tailed t test. (E) From the CD11b+ gating, relative abundance of Ly6C– CD64+ macrophages in lung tissue. (F–H) From the CD64– gating, relative frequency of dendritic cells in lung tissue: MHCIIhiCD11Chi (F), MHCIIhiCD11Clo (G), and MHCIIloCD11Chi (G). (I–L) From the CD45+ population, relative frequency of NKP46+ NK cells (I), CD3+ T cells (J), CD4+ T helper cells (K), and CD8+ CTLs (L). (M–O) From the CD45+CD11b+ cells, purity check of circulating monocytes in peripheral blood (M). Relative frequency of circulating monocytes: Ly6ChiCD64– (N) and Ly6ChiCD64+ (O). Data are represented as mean with SEM. *P < 0.05; **P < 0.01; ****P < 0.0001, 1-way ANOVA with Bonferroni’s post hoc test for the comparisons between ALK1-Fc versus ALK1-Fc + IT and IT versus ALK1-Fc + IT.