Immune microenvironment in breast cancer bone metastasis
Item statusRestricted Access
Embargo end date31/07/2022
Bone metastasis is the major cause of death in breast cancer. However, the underlying mechanisms of bone metastasis progression are still largely unknown. The role of the tumour microenvironment in metastatic progression has been increasingly appreciated in recent years. As one of the major immune components of the tumour microenvironment, macrophages promote breast tumour progression and lung metastasis. In patient bone metastasis samples and preclinical in vivo models, I found that macrophages abundantly infiltrate in bone metastasis. The macrophage depletion assays significantly inhibit bone metastasis growth, showing the critical role of macrophages in bone metastasis growth. I noticed that heterogeneous macrophage populations in bone metastatic lesions and a specific subset of macrophages infiltrated inside tumours were identified by high expression of CD204 and IL-4R. Lineage tracking of macrophages showed they were recruited from circulating monocytes via CCL2/CCR2 chemokine signalling. Blocking their recruitment led to a significant delay of bone metastasis onset and inhibition of tumour growth. Furthermore, genetic ablation of IL-4R inhibits bone metastasis. To better understand the CD204hi bone metastasis-associated macrophage (BoMAMs) subset, I performed RNA sequencing to compare the transcriptional change of macrophages with high and low expression of CD204 in bone metastasis, as well as macrophages from healthy bone marrow with high CD204 expression. The results revealed the changes of CD204hi BoMAMs at the molecular level including the increased expression of wound healing, immunosuppressive and tissue remodelling related genes. These results provided several candidate genes that may benefit drug design. Meanwhile, I profiled the change of haematopoietic cell populations in bone metastasis progression using single-cell RNA sequencing. The data showed a significant difference of immune cell populations in early and late bone metastasis stages compared with normal bone. Several immune cell populations showed remarkable reductions including B cells and T cells, while neutrophils increased during metastasis growth. Interestingly, erythroid progenitors largely increased in the early stage of bone metastasis, which may promote the initial growth of bone metastasis. In summary, these studies identified the critical role of a monocyte-derived macrophage subset in promoting breast cancer bone metastasis. The macrophage subset is regulated by the CCL2/CCR2 axis and IL-4R signalling pathway. The BoMAMs highly upregulated wound healing and immunosuppressive related genes. In addition, I found other haematopoietic cell populations were also affected in bone metastasis. Apart from macrophages, erythroid progenitors may also play an important role in tumour growth. Together, these results provide several potential therapeutic targets to treat breast cancer bone metastasis.