Breast cancer remodels the bone marrow lymphoid microenvironment to favor bone metastasis 3812

Abstract Description Bone is the most common site of breast cancer metastasis, occurring in 70% of patients, and an indication of short-term prognosis. Bone colonization by cancer cells is a stepwise process that relies on interactions between tumor cells and the bone microenvironment. While it is well established that host immunity plays a fundamental role in tumorigenesis, the role of immune cells in bone metastasis remains poorly understood. Using immunocompetent mouse models of breast cancer bone metastasis, we found that breast cancer profoundly transforms the bone marrow lymphoid microenvironment before the arrival of tumor cells and induces bone lymphoid cell loss, with a dramatic reduction of B cells, the most abundant bone marrow lymphoid subset. Additionally, breast cancer induces an expansion of lymphoid progenitors with a reprogrammed transcriptional landscape and impaired differentiation capacity. Of note, single cell analysis showed that the remaining B cells present in the bone marrow exhibit reduced activation, maturation, antigen processing and presentation. Importantly, depletion of mature B cells increases bone metastasis incidence, suggesting that B cell loss creates a vulnerable bone environment prone to tumor cell colonization. Overall, our data reveals that breast cancer cells distantly shape B cell trajectories and imprint specific molecular programs in B cell progenitors that enhance metastasis, and identifies B cells as potential therapeutic targets in bone metastasis. Funding Sources This work was supported by the Division of Intramural Research of NIAID (NIAID; 1ZIA-AI001115 and 1ZIA- AI001132). A.T. was supported by the EMBO Postdoctoral Fellowship ALTF 1014-2021. Topic Categories Hematopoiesis and Immune System Development (HEM)