Cooperation between T and B cells reinforce the establishment of bone metastases in a mouse model of breast cancer

Abstract

Immune cells educated by the primary breast tumor and their secreted factors support the formation of bone pre-metastatic niche. Indeed, we showed that RANKL⁺ CD3⁺ T cells, specific for the 4T1 mammary carcinoma cell line, arrive at the bone marrow before metastatic cells and set the pre-metastatic niche. In the absence of RANKL expressed by T cells, there is no pre-metastatic osteolytic disease and bone metastases are completely blocked. Adding to the role of T cells, we have recently demonstrated that dendritic cells assist RANKL⁺ T cell activities at bone pre-metastatic niche, by differentiating into potent bone resorbing osteoclast-like cells, keeping their antigen-presenting cell properties, providing a positive feedback loop to the osteolytic profile. Here we are showing that bone marrow-derived CD19⁺ B cells, from 4T1 tumor-bearing mice, also express the pro-osteoclastogenic cytokine receptor activator of NFκB ligand (RANKL). Analysis of trabecular bone mineral density by conventional histomorphometry and X-ray microtomography (micro-CT) demonstrated that B cells expressing RANKL cooperate with 4T1-primed CD3⁺ T cells to induce bone loss. Moreover, RANKL expression by B cells depends on T cells activity, since experiments performed with B cells derived from 4T1 tumor-bearing nude BALB/c mice resulted in the maintenance of trabecular bone mass instead of bone loss. Altogether, we believe that 4T1-primed RANKL⁺ B cells alone are not central mediators of bone loss in vivo but when associated with T cells induce a strong decrease in bone mass, accelerating both breast cancer progression and bone metastases establishment. Although several studies performed in different pathological settings, showed that B cells, positively and negatively impact on osteoclastogenesis, due to their capacity to secret pro or anti-osteoclastogenic cytokines, as far as we know, this is the first report showing the role of RANKL expression by B cells on breast cancer-derived bone metastases scenario.

Keywords: And osteolytic disease; B cells; Bone metastases; Breast cancer; Breast tumor; Osteoclasts; Pre-metastatic niche; RANKL; T cells.