Abstract
While macrophages are among the most abundant immune cell type found within primary and metastatic mammary tumors, how their complexity and heterogeneity change with metastatic progression remains unknown. Here, macrophages were isolated from the lungs of mice bearing orthotopic mammary tumors for single-cell RNA sequencing (scRNA-seq). Seven distinct macrophage clusters were identified, including populations exhibiting enhanced differential expression of genes related to antigen presentation ( H2-Aa, Cd74), cell cycle ( Stmn1, Cdk1), and interferon signaling ( Isg15, Ifitm3). Interestingly, one cluster demonstrated a profile concordant with lipid-associated macrophages ( Lgals3, Trem2). Compared with nontumor-bearing controls, the number of these cells per gram of tissue was significantly increased in lungs from tumor-bearing mice, with the vast majority costaining positively with the alveolar macrophage marker Siglec-F. Enrichment of genes implicated in pathways related to lipid metabolism as well extracellular matrix remodeling and immunosuppression was observed. In addition, these cells displayed reduced capacity for phagocytosis. Collectively, these findings highlight the diversity of macrophages present within metastatic lesions and characterize a lipid-associated macrophage subset previously unidentified in lung metastases. SIGNIFICANCE: scRNA-seq of macrophages isolated from lung metastases reveals extensive macrophage heterogeneity and identifies a novel subpopulation enriched for genes involved in lipid metabolism, extracellular matrix remodeling, and immunosuppression.
| Original language | English (US) |
|---|---|
| Journal | Cancer Research |
| Volume | 81 |
| Issue number | 20 |
| DOIs | |
| State | Published - Oct 15 2021 |
Bibliographical note
Funding Information:The authors thank Dr. Thomas Griffith (University of Minnesota) for providing the 4T1-Luc cells and Dr. Jeffrey Rosen (Baylor College of Medicine) for providing the initial HC11/R1 cells. We thank the University of Minnesota Genomics Center, Flow Cytometry Resource, and Center for Immunology Imaging Facility for expertise and contributions to this work. Funding for this work was provided by an American Cancer Society Postdoctoral Fellowship (PF-18-140-01-CSM) to DNH; R00HL138163 to JWW; R21CA235285, R01CA215052, and R01HD095858 to KLS.
Funding Information:
was provided by an American Cancer Society Postdoctoral Fellowship (PF-18-140-01-CSM) to
Funding Information:
The authors thank Dr. Thomas Griffith (University of Minnesota) for providing the 4T1-Luc cells and Dr. Jeffrey Rosen (Baylor College of Medicine) for providing the initial HC11/R1 cells. We thank the University of Minnesota Genomics Center, Flow Cytometry Resource, and Center for Immunology Imaging Facility for expertise and contributions to this work. Funding for this work
Publisher Copyright:
© 2021 American Association for Cancer Research.
Keywords
- Breast cancer
- Lung metastasis
- Macrophage
- Single-cell RNA sequencing
- Tumor microenvironment
