Emerging Roles of Osteoclasts in the Modulation of Bone Microenvironment and Immune Suppression in Multiple Myeloma

Abstract

Multiple myeloma (MM) is one of the most common forms of hematologic malignancy resulting from cancerous proliferation of mature malignant plasma cells (MPCs). But despite the real improvement in therapeutics in the past years, it remains largely incurable. MM is the most frequent cancer to involve bone due to the stimulation of osteoclast (OCL) differentiation and activity. OCLs have a unique capacity to resorb bone. However, recent studies reveal that they are not restrained to this sole function. They participate in the control of angiogenesis, medullary niches, and immune responses, including in MM. Therefore, therapeutic approaches targeting OCLs probably affect not only bone resorption but also many other functions, and OCLs should not be considered anymore only as targets to improve the bone phenotype but also to modulate bone microenvironment. In this review, we explore these novel contributions of OCLs to MM which reveal their strong implication in the MM physiopathology. We also underline the therapeutic interest of targeting OCLs not only to overcome bone lesions, but also to improve bone microenvironment and anti-tumoral immune responses.

Keywords: hematopoietic niche; immunomodulation; multiple myeloma; myeloma bone disease; osteoclast; osteoimmunology.

Figure 1

Osteoclast (OCL) development in steady state and multiple myeloma (MM). (A) In steady state, osteoclasts (OCLs) derive from monocytes (MN) under the influence of M-CSF and RANKL produce by osteoblasts (OBLs) and mesenchymal stromal cells (MSCs). (B) In MM environment, malignant plasma cells (MPC) produce and stimulate the production of RANKL by MSCs leading to a higher OCL differentiation. In the presence of such high levels of RANKL and IL-17 produced by Th17 cells, OCLs arise not only from MNs but also from dendritic cells (DCs). Moreover, MPCs form OCL-like polycaryons in the presence of high RANKL levels. Combination of these mechanisms lead to a dramatic increase of OCLs and to bone lesions.

Figure 2

Contribution of osteoclasts (OCLs) to multiple myeloma (MM). OCLs may contribute to MM through different mechanisms. Producing proteases and proton, they are responsible not only for bone lesions but also for remodeling the endosteal niches and controlling the maintenance of dormant malignant plasma cells (MPCs). They also promote angiogenesis required for tumor cell survival and proliferation and tumor progression. Subsets of OCLs produce immunosuppressive cytokines and induce regulatory T (Treg) cells in an antigen-dependent manner. Lastly, OCLs express checkpoint proteins that participate in the inhibition of CTLs and suppression of T cell activation.