Fig. 2.

The interaction between immune cells and tumor cells during bone metastasis. Under the innate arm of the immune system, macrophages, dendritic cells (DCs), neutrophils, and myeloid-derived suppressor cells (MDSCs) release pro-tumorigenic cytokines that aid in the successful establishment of disseminated tumor cells (DTCs) in bone. Natural killer (NK) cells, however, deploy anti-tumorigenic cytokines that promote tumor regression. On the other hand, CD4 + T cells and Bregs release certain cytokines that stimulate cancer cells to metastasize to bone. Differentiation of CD8 + T cells into cytotoxic T lymphocytes (CTLs) exert anti-tumoral attack by secretion of proinflammatory cytokines- TNF-α and IFN-γ, consequently an anti-metastatic effect. As shown in the figure, the osteolytic tumor cells majorly release pro-osteoclastogenic cytokines such as receptor activator for nuclear factor kappa-B ligand (RANKL), parathyroid hormone-related protein (PTHrP), and C-X-C Chemokine Receptor 4 (CXCR4) which activate osteoclastogenesis and drive formation of osteolytic lesion.