Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 217, Issue 11, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20191820
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Funding
- Cancer Research UK [C49791/A17367]
- European Research Council [716379]
- National Natural Science Foundation of China [81872150]
- National Cancer Institute [P30CA013330, RO1CA131270]
- Wellcome Trust [101067/Z/13/Z]
- Edinburgh Global Research scholarship
- Medical Research Council Centre grant [MR/N022556/1]
- MRC [MR/N022556/1] Funding Source: UKRI
- European Research Council (ERC) [716379] Funding Source: European Research Council (ERC)
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Bone metastasis is the major cause of death in breast cancer. The lack of effective treatment suggests that disease mechanisms are still largely unknown. As a key component of the tumor microenvironment, macrophages promote tumor progression and metastasis. In this study, we found that macrophages are abundant in human and mouse breast cancer bone metastases. Macrophage ablation significantly inhibited bone metastasis growth. Lineage tracking experiments indicated that these macrophages largely derive from Ly6C(+)CCR2(+) inflammatory monocytes. Ablation of the chemokine receptor, CCR2, significantly inhibited bone metastasis outgrowth and prolonged survival. Immunophenotyping identified that bone metastasis-associated macrophages express high levels of CD204 and IL4R. Furthermore, monocyte/macrophage-restricted IL4R ablation significantly inhibited bone metastasis growth, and IL4R null mutant monocytes failed to promote bone metastasis outgrowth. Together, this study identified a subset of monocyte-derived macrophages that promote breast cancer bone metastasis in an IL4R-dependent manner. This suggests that IL4R and macrophage inhibition can have potential therapeutic benefit against breast cancer bone disease.
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