An activin receptor-like kinase 1–governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases
Mehrnaz Safaee Talkhoncheh, … , Matteo Bocci, Kristian Pietras
Mehrnaz Safaee Talkhoncheh, … , Matteo Bocci, Kristian Pietras
Published January 14, 2025
Citation Information: J Clin Invest. 2025;135(5):e183086. https://doi.org/10.1172/JCI183086.
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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 3

ACVRL1-expressing TAMs display an immunosuppressive phenotype associated with resistance to therapy and poor survival.

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ACVRL1-expressing TAMs display an immunosuppressive phenotype associated...
(A and B) Survival analysis in the TCGA BRCA (37) (A) and METABRIC (38) (B) datasets. Patients were stratified into 2 risk groups based on the median value of the mean expression of a TAM-specific ACVRL1 signature. The Kaplan-Meier curves show the DSS probabilities of the high (red) and low (green) signature expression groups in the 2 cohorts. P value: log-rank test. The tables summarize the relative Cox’s proportional hazard model analysis for each cohort. (C and D) Box plots depicting the expression of ACVRL1 (C) and the 5-gene signature of ACVRL1+ macrophages (D) in a bulk RNA-Seq dataset of 43 TNBC patients sequenced before treatment with anti–PD-1 (41). Pretreatment features were then correlated to response to therapy (responders, n = 16; nonresponders, n = 27). Statistical analysis was performed using Wilcoxon’s rank sum test, and the P values were corrected for multiple testing with the Benjamini-Hochberg method. (E and F) Expression of ACVRL1 in a CD45+-restricted scRNA-Seq compendium of 48 melanoma patients treated with immune checkpoint inhibitors (40). The average expression of the 5-gene signature, and the average scaled expression of the individual genes are presented in a heatmap (E) based on response, time point, and treatment arm. The average expression of ACVRL1 in the combined CTLA-4 and PD-1 inhibition group was imposed on the UMAP, and further split to create 4 different groups: preresponder, postresponder, prenonresponder, and postnonresponder (F). Contingent on the aggregated data points in F, the average scaled expression of the 5 genes comprised in the ACVRL1 signature is presented in a heatmap (G).