Effects of RANKL-Targeted Therapy in Immunity and Cancer

Abstract

The role of the receptor activator of nuclear factor-κB ligand (RANKL)/RANK system is well characterized within bone, where RANKL/RANK signaling mediates osteoclastogenesis and bone resorption. However, this system has also been shown to influence biologic processes beyond the skeletal system, including in the immune system and in cancer. RANKL/RANK signaling is important in lymph-node development, lymphocyte differentiation, dendritic cell survival, T-cell activation, and tolerance induction. The RANKL/RANK axis may also have direct, osteoclast-independent effects on tumor cells. Indeed, activity of the RANKL/RANK pathway in cancer cells has been correlated with tumor progression and advanced disease. Denosumab, a fully human monoclonal antibody against RANKL, inhibits osteoclastogenesis and is widely used not just for the treatment of osteoporosis, but for the prevention of skeletal-related events from bone metastases in solid malignancies such as breast and prostate cancer. The potential effects of denosumab on the immune system have been largely ignored. Nevertheless, with the emergence of immunotherapies for cancer, denosumab may impact the effectiveness of these therapies, especially if they are given in combination. In this article, we review the role of RANKL/RANK in bone, immunity, and cancer. Examining the potential effects of routine treatment with denosumab beyond the bone represents an important area of investigation.

Keywords: RANK ligand; T-cell activation; cancer immunology; dendritic cells; denosumab; immune tolerance; prostate cancer; receptor activator of nuclear factor-kappa B.

Figure 1

RANKL/RANK signaling in osteoclast formation and DC activation. (A). RANKL/RANK interactions enhances osteoclast differentiation and bone resorption. (B) RANKL/RANK interactions also occur in the immune system, driving dendritic cell survival, and activation. (C) Signaling occurs via the recruitment of adaptor molecules, most importantly TNF receptor-associated factor 6 (TRAF6), which activates downstream signaling pathways, including that of nuclear factor-κB (NFκB) as well as mitogen-associated protein kinases (MAPK) such as p38, c-Jun N-terminal protein kinases (JNK), and the extracellular signal-regulated kinases (ERK). TRAF6 also complexes with c-Src to activate the antiapoptotic serine/threonine kinase AKT/PKB. (D) Immature interstitial DCs co-express both RANKL and RANK, and demonstrate autocrine stimulation. However, as these cells mature, they down-regulate RANKL and become dependent on exogenous factors.