Contribution of the immune bone marrow microenvironment to tumor growth and bone deconstruction: implications for improving immunotherapeutic strategies in bone metastasis

Abstract

Bone metastases are frequent complications of many solid tumors, leading to painful skeletal morbidities and increasing mortality for patients with advanced cancer. Once in bone, cancer cells deregulate bone homeostasis, altering the functions of bone-forming (osteoblasts) and bone-resorbing (osteoclasts) cells, which results in skeletal deconstruction. Aside from bone cells, cancer cells in the bone marrow interact with other cell populations, including immune cells that also play an integral part in the regulation of bone homeostasis. In this respect, immune checkpoint inhibitors (ICIs) have become a standard of care in immunotherapy for the treatment of patients with advanced cancer. Strikingly, however, those with bone metastases have a shorter survival when treated with ICIs than ICI-treated cancer patients without bone metastases. In this Review, after presenting the immune cells involved in bone metastasis, we review preclinical and clinical findings assessing ICI efficacy both in bone and extraosseous metastases, and we discuss the clinical utility of using bone-targeted agents -including denosumab and bisphosphonates- to improve anti-tumoral efficacy of ICI treatments in patients with cancer and bone metastases.

Keywords: Bone metastasis; Bone resorptive agents; Immunity; Immunotherapy; Micro-environment.

Fig. 1

Distinct roles of immune cells in the bone tumor microenvironment. Left-hand panel: several immune cells work to destroy tumor cells: NK cells release granzyme and perforin, which directly induce tumor cell lysis. CD4+ Th1, γδ T and CD8+ T cells secrete IFNγ, a cytokine that enhances the immune response by activating other immune cells and promoting tumor cell death. CD8+ T cells also produce granzyme and perforin, mediating direct cytotoxicity. M1 macrophages produce pro-inflammatory cytokines like IL-1, IL-6, and TNFα, which support inflammation and anti-tumor responses, and they also phagocyte tumor cells. N1 neutrophils and conventional dendritic cells (cDCs) contribute to the direct tumor cells elimination through immune activation. Right-hand panel: specific immune cells promote tumor growth by suppressing the anti-tumor immune response. M2 macrophages and immature myeloid-derived suppressor cells (iMDSCs) secrete IL-10, an immunosuppressive cytokine that dampens anti-tumor immune responses, allowing tumor cells to evade immune surveillance. Tregs produce IL-10, which inhibits the activity of other immune cells. Plasmacytoid dendritic cells (pDCs) release TGFβ, a cytokine that suppresses immune responses and promotes tumor growth. N2 neutrophils further contribute to immune suppression by supporting a pro-tumoral environment. Overall, this figure illustrates the dynamic balance between immune cells that actively fight tumor cells and those that create an immune suppressive microenvironment, enabling tumor cells growth.