Beyond immunosuppressive effects: dual roles of myeloid-derived suppressor cells in bone-related diseases

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells (IMCs) with immunosuppressive functions, whereas IMCs originally differentiate into granulocytes, macrophages, and dendritic cells (DCs) to participate in innate immunity under steady-state conditions. At present, difficulties remain in identifying MDSCs due to lacking of specific biomarkers. To make identification of MDSCs accurately, it also needs to be determined whether having immunosuppressive functions. MDSCs play crucial roles in anti-tumor, angiogenesis, and metastasis. Meanwhile, MDSCs could make close interaction with osteoclasts, osteoblasts, chondrocytes, and other stromal cells within microenvironment of bone and joint, and thereby contributing to poor prognosis of bone-related diseases such as cancer-related bone metastasis, osteosarcoma (OS), rheumatoid arthritis (RA), osteoarthritis (OA), and orthopedic trauma. In addition, MDSCs have been shown to participate in the procedure of bone repair. In this review, we have summarized the function of MDSCs in cancer-related bone metastasis, the interaction with stromal cells within the bone microenvironment as well as joint microenvironment, and the critical role of MDSCs in bone repair. Besides, the promising value of MDSCs in the treatment for bone-related diseases is also well discussed.

Keywords: Bone metastasis; Bone microenvironment; Bone repair; Inflammatory arthritis; MDSCs; Osteoimmunology.

Fig. 1

The role of MDSCs in bone metastasis. Initially, MDSCs promote EMT of primary tumor cells via IL-6-STAT3, TGF-β1/Smad as well as NF-κB signaling. Besides, MDSCs trigger the expression of miRNA101 in tumor cells, which subsequently inhibits the CtBP2. Then, MDSCs secrete TGF-β, Arg-1, ROS, COX-2, Bv8, MMP-9, S100A8, S100A9, and OPN, which are involved in the formation and evolution of multiple features of PMN, and PMN provide a favorable survival environment for disseminated tumor cells. In addition, MDSCs can also lay an important role in the growth phase of tumors via the release of VEGF, bFGF, VEGF analogues Bv8, MMP-9, and OPN to regulate the tumor microenvironment at the metastatic site. Reciprocally, tumor cells secrete MCP-1, IL-1, IL-6, IL-10, TNF-α, and OPN to promote MDSCs. MDSCs differentiate into osteoclasts through HIF-1α signaling or express MMP-9 to induce osteoclasts migration. In addition, MDSCs may also stimulate endogenous macrophages to differentiate into osteoclasts by secreting NO, IL-1, IL-6, M-CSF. Osteoblasts also promote the release and activation of MDSCs through upregulating VEGF-A, IL-6, and EDA-FN. In addition, osteoblasts and osteoclasts also produce OPN to act on MDSCs as well as tumor cells. Moreover, MDSCs dampen T cells to secret osteoclastogenesis inhibitors, including IFN-γ, IL-4, and IL-10, thereby indirectly boosting the process of bone resorption

Fig. 2

The role of MDSCs in the bone microenvironment and joint microenvironment when rheumatoid arthritis. In the bone microenvironment, MDSCs, with the help of other immune cells and cytokines, directly or indirectly interact with osteoclasts and osteoblasts to induce bone loss. The immune cells include Th17 cells, Treg cells, macrophages, and the cytokines include pro-osteoclastogenesis factors (TGF-β, IL-1β, M-CSF, RANKL, IL-1α, NF-κB, IL-6, TNF-α) and anti-osteoclastogenesis factors (CTLA-4, GM-CSF, IFN-γ, IL-5, IL-10, TGF-β, MAPK, Smad, Wnt10b). In the joint microenvironment, on one hand, MDSCs play a pro-inflammatory role by promoting Th17 cells. And various pro-inflammatory cytokines are involved, including IL-1β, IL-6, IL-26, IL-17A, IL-17F, IL-22, IL-23, TNF-α, and GM-CSF. On the other hand, MDSCs paly an anti-inflammatory role through the interaction with Th17 cells, Treg cells, macrophages, chondrocytes. Besides, anti-inflammatory factors such as TNF-α, IL-1β, IL-6, and IL-10 are involved in the interaction

Fig. 3

The therapeutic strategies for cancer-related bone metastasis by targeting MDSCs. Based on the principles for MDSCs-targeted immune therapies that we have discussed, therapeutic strategies for cancer-related bone metastasis by targeting MDSCs fall into five main groups. Starting from the section with blue as the background color, five therapeutic strategies are shown clockwise. The strategies include: a limiting the generation, recruitment, and localization of MDSCs, b impeding the immunosuppressive function of MDSCs, c blocking the effect of MDSCs on PMN formation, d targeting MDSCs death pathway, e suppressing the osteoclastogenesis of MDSCs