Roles of the RANKL–RANK Axis in Immunity—Implications for Pathogenesis and Treatment of Bone Metastasis

Abstract

A substantial amount patients with cancer will develop bone metastases, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis. Despite advancements in systemic therapies for advanced cancer, survival remains poor for those with bone metastases. The interaction between bone cells and the immune system contributes to a better understanding of the role that the immune system plays in the bone metastasis of cancer. The immune and bone systems share various molecules, including transcription factors, signaling molecules, and membrane receptors, which can stimulate the differentiation and activation of bone‐resorbing osteoclasts. The process of cancer metastasis to bone, which deregulates bone turnover and results in bone loss and skeletal-related events (SREs), is also controlled by primary cancer-related factors that modulate the intratumoral microenvironment as well as cellular immune process. The nuclear factor kappa B ligand (RANKL) and the receptor activator of nuclear factor kappa B (RANK) are key regulators of osteoclast development, bone metabolism, lymph node development, and T-cell/dendritic cell communication. RANKL is an osteoclastogenic cytokine that links the bone and the immune system. In this review, we highlight the role of RANKL and RANK in the immune microenvironment and bone metastases and review data on the role of the regulatory mechanism of immunity in bone metastases, which could be verified through clinical efficacy of RANKL inhibitors for cancer patients with bone metastases. With the discovery of the specific role of RANK signaling in osteoclastogenesis, the humanized monoclonal antibody against RANKL, such as denosumab, was available to prevent bone loss, SREs, and bone metastases, providing a unique opportunity to target RANKL/RANK as a future strategy to prevent bone metastases.

Extensive plasma proteomic profiling revealed receptor activator of nuclear factor kappa-Β ligand (RANKL) as emerging biomarker of nivolumab clinical benefit in patients with metastatic renal cell carcinoma

“…In tumor microenvironment, RANKL signaling play a key role in modulating the immunological niche inducing T cell and NK suppression and promoting regulatory T cells or MDSCs activation. [25][26][27] Taken together, these evidences partially explain how RANKL could affects antitumor responses of the immune system supporting our findings. As previously mentioned, our exploratory study included a small number of patients, but it was adequately powered to screen the potential prognostic/predictive role of soluble molecules (discovery set) and to confirm the magnitude of differences observed in RANKL levels (validation set).…”

Bone Metastasis and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC): Microenvironment and Possible Clinical Implications

“…Naturally, the RANKL-RANK-OPG (osteoprotegerin) pathway remains the central mechanism of osteolytic metastasis [ 24 , 25 ]. Since RANKL is also expressed in immuno-cells such as NK and T cells, the RANK/OPG balance regulates lymphocyte development in the lymph nodes, maintains dendritic cell activation, and regulates the mediated T response [ 26 ].…”

Bone Metastasis of Breast Cancer: Molecular Mechanisms and Therapeutic Strategies

“…RANKL was originally identified in the mouse thymoma cell line EL40.5. A genomic analysis identified RANKL as a DC stimulator expressed by activated T cells [ 122 ], and RANKL was reported to be involved in regulating the interaction between T cells and DCs [ 123 ]. The selective activation and suppression of immunity by the RANKL–RANK interaction depend on the tissue location and pathophysiological background.…”