The Contribution of the Immune System in Bone Metastasis Pathogenesis

Abstract

Bone metastasis is associated with significant morbidity for cancer patients and results in a reduced quality of life. The bone marrow is a fertile soil containing a complex composition of immune cells that may actually provide an immune-privileged niche for disseminated tumor cells to colonize and proliferate. In this unique immune milieu, multiple immune cells including T cells, natural killer cells, macrophages, dendritic cells, myeloid-derived suppressor cells, and neutrophils are involved in the process of bone metastasis. In this review, we will discuss the crosstalk between immune cells in bone microenvironment and their involvement with cancer cell metastasis to the bone. Furthermore, we will highlight the anti-tumoral and pro-tumoral function of each immune cell type that contributes to bone metastasis. We will end with a discussion of current therapeutic strategies aimed at sensitizing immune cells.

Keywords: bone metastasis; immune system; immunotherapy.

Figure 1

The interaction of immune cells and cancer cells during bone metastasis. Cytotoxic CD8⁺ T cells release TNF-α and IFN-γ to eliminate tumor cells. Natural killer cells (NK cells) kill tumor cells through granzyme B- and perforin-mediated apoptosis. Regulatory T cells (Tregs) promote tumor cell to bone metastasis through CXCR4/CXCL12 signaling or RANK/RANKL axis. Tumor-associated macrophages (TAMs) promote tumor cell to bone metastasis through CCL2/CCR2 or CSF-1/ CSF-1R signaling. Meanwhile, TAMs secret high levels of IL-10 and TGF-β to decrease the activation of CD4⁺ and CD8⁺ T cells. Dendritic cells (DCs) suppress the cytotoxic capacity of CD8⁺ T cells via production of arginase I, nitric oxide (NO), TGF-β, interleukin-10 (IL-10) to promote tumor progression. Myeloid-derived suppressor cells (MDSCs) release chemokines including IL-6, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and matrix metalloproteinase (MMP)-9 to promote cancer progression and bone metastasis. Tumor-associated neutrophils (TANs) are able to release CXCR4, VEGF and MMP9 to promote tumor bone metastasis. Tumor cells also release factors such as RANK, E-cadherin, CXCR4, and parathyroid hormone-related protein (PTHrP) that promote osteolytic bone lesions.