Medical Research Council Centre for Reproductive Health, College of Medicine and Veterinary Medicine, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, NY.
J Exp Med. 2020 Nov 2;217(11). doi: 10.1084/jem.20191820.
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.
骨转移是乳腺癌患者死亡的主要原因。缺乏有效的治疗方法表明，疾病机制在很大程度上仍不为人知。作为肿瘤微环境的关键组成部分，巨噬细胞促进肿瘤的进展和转移。在这项研究中，我们发现巨噬细胞在人类和小鼠乳腺癌骨转移中大量存在。巨噬细胞消融显著抑制了骨转移的生长。谱系追踪实验表明，这些巨噬细胞主要来源于 Ly6C+CCR2+炎性单核细胞。趋化因子受体 CCR2 的消融显著抑制了骨转移的生长并延长了生存期。免疫表型分析确定与骨转移相关的巨噬细胞表达高水平的 CD204 和 IL4R。此外，单核细胞/巨噬细胞特异性的 IL4R 消融显著抑制了骨转移的生长，而 IL4R 缺失型单核细胞则不能促进骨转移的生长。总之，这项研究确定了一组以 IL4R 依赖性方式促进乳腺癌骨转移的单核细胞衍生的巨噬细胞亚群。这表明 IL4R 和巨噬细胞抑制可能对乳腺癌骨疾病具有潜在的治疗益处。
