Immune system and bone microenvironment: rationale for targeted cancer therapies

Abstract

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator of NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.

Keywords: antiandrogens; bisphosphonates; bone niche; immune system; osteoimmunology.

Figure 1. An example of interaction between bone, immune and cancer cells: osteoclastogenesis, mechanism of bone resorption and potential targets of biphosphonates and denosumab.

The complex process of osteoclastogenesis in cancer is regulated by an interaction between bone, immune and cancer cells. Cancer cells promote this process in two ways: 1) indirectly, stimulating osteoblast to activate the RankL/Rank pathway (bone osteoclastogenesis) and deregulating immune cells activity against osteoclasts; 2) directly, stimulating osteoclastsogenesis by upregulation of IL-1, IL-6, PTHrP, GM-CSF. After cancer cells signals, immune system cells activate osteoclastogenesis by upregulation of TNFa, IL-1a, IL-1b, IL-7, IL-8, IL-23. Once activated, osteoclasts protect their growth with the inactivation of immune system by TGF-beta production. Bisphosphonates (i.e. Zoledronic Acid) inhibit osteoclast formation, recruitment and adhesion to bone shift the balance towards OPG production by osteoblasts and induce osteoclasts apoptosis. Denosumab is a fully human monoclonal antibody with anti-RANKL activity, thus inhibiting osteoclast activation by Rank receptor. Initial data evidenced a possible role in immune system preservation by B cell/T cell differentiation and dendritic cell survival.