Immune Checkpoint Inhibitor Therapy for Bone Metastases: Specific Microenvironment and Current Situation

Abstract

The treatment of bone metastases is a thorny issue. Immunotherapy may be one of the few hopes for patients with unresectable bone metastases. Immune checkpoint inhibitors are the most commonly used immunotherapy drugs currently. In this review, the characteristics and interaction of bone metastases and their immune microenvironment were systematically discussed, and the relevant research progress of the immunological mechanism of tumor bone metastasis was reviewed. On this basis, we expounded the clinical application of immune checkpoint inhibitors for bone metastasis of common tumors, including non-small-cell lung cancer, renal cell carcinoma, prostate cancer, melanoma, and breast cancer. Then, the deficiencies and limitations in current researches were summarized. In-depth basic research on bone metastases and optimization of clinical treatment is needed.

Figure 1

The difference between peripheral blood and bone marrow immune microenvironment. Compared with peripheral blood, there are a large number of immature and suppressive immune cell types in the bone marrow. CD4+ T cells, CD8+ T cells, NK cells, and other immune effector cells accounted for a small proportion, while immunosuppressive Treg cells and MDSCs accounted for a large proportion, which not only protected hematopoietic stem cell (HSC) but also weakened the immune killing effect on tumor cells. It provides an immune-privileged niche for disseminated tumor cells. A large number of immune factors are involved in the formation and regulation of osteoblasts and osteoclasts, which also affect the immune microenvironment of bone marrow.

Figure 2

The interaction among the bone, immune system, and cancer cells. Tumor cells secrete PTHrP, PGE2, and other substances, which promote the transformation of osteoblasts into osteoclast precursors through the RANKL pathway and then differentiate into osteoclasts, causing bone destruction. Tumors can induce the release of CCl2 from the osteoclast precursors through the PD-1 pathway, which again promotes the occurrence of RANKL-induced osteoclasts. Osteoclasts secrete IDO-1, IL-10, and other substances to induce immunosuppression. TGF-β released by the destruction of bone and IL-6 in the microenvironment also causes immunosuppression. T cells differentiate into T_h17 and Treg instead of T_h1, forming an immune-hostile (cold) tumor microenvironment. T_h17 secretes IL-17 and IFN-γ to promote osteoclast differentiation, while Treg cells rely on the CTLA-4 pathway to inhibit the transformation of osteoclast precursors to osteoclasts. PTHrP: parathyroid hormone-related peptide; PGE2: prostaglandin E2; CCI2: chemokine (C-C motif) ligand 2; IDO-1: indoleamine 2,3-dioxygenase 1; IL: interleukin; TGF-β: transforming growth factor-β; IFN-γ: interferon-γ.