Breast cancer remodels the bone marrow immune microenvironment to favor bone metastasis

Abstract Bone is the most common site of breast cancer (BC) metastasis, occurring in 70% of patients, and an indication of short-term prognosis. Understanding the environmental and host factors involved in the induction of metastasis is essential to develop therapies that extend patient’s lifespan. Bone colonization by cancer cells is a stepwise process that relies on interactions between cancer cells and the cells that comprise the bone microenvironment, such as osteoclasts, osteoblasts, hematopoietic cells, immune cells, and adipocytes. Calcium, growth factors, and chemokines facilitate bone metastasis. However, the role of immune cells in bone metastasis remains poorly understood. Further, how physiological stressors such as nutrition contribute to pro- or anti-metastatic bone immunity remains unclear. Using mouse models of BC, we found that BC profoundly transforms the bone marrow (BM) immune microenvironment to support metastasis. BC induces bone lymphoid cell loss, with significant reduction in B cells, T cells and NK cells. On the other hand, mammary tumors are associated with enhanced monocytes and eosinophils within the BM. These results support the idea that BC cells crosstalk with the bone and remodel the immune microenvironment to favor tumor cell colonization. We have previously showed that caloric restriction (CR) induces T cell migration to the BM and remodels the bone microenvironment, favoring T cell function and a protective environment. Of note, CR-mediated targeting of the bone microenvironment restores the immune homeostatic pool and contributes to an anti-tumor bone immunity. Thus, nutritional interventions my represent potential therapeutic strategies to target bone metastasis. This work was supported in part by intramural funds of NIAID, NIH. A.T. is supported by the EMBO Postdoctoral Fellowship Programme (ALTF 1014-2021).