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.

Bone Metastasis and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC): Microenvironment and Possible Clinical Implications

“…We know that the differentiation of pre-osteoblasts into osteoclasts occurs through cytokines derived from the immune system, such as macrophage colony-stimulating factor (M-CSF), interleukins (IL), transforming grow factor beta (TGF-beta), prostaglandins, and interferon gamma. Conversely, bone cells regulate immune cells by creating the so-called “endosteal niche” [ 19 , 20 ].…”

“…Tumor cells themselves release cytokines, which break the balance between osteoblasts and osteoclasts, thereby causing bone resorption and creating an immunosuppressive microenvironment—the so-called “vicious cycle” [ 19 , 21 ] ( Figure 1 ). Cancer cells, in fact, secrete parathyroid hormone-related peptide (PTHrP), prostaglandin E2 (PGE2), and other substances that promote the transformation of osteoblasts into pre-osteoclasts through the receptor-activator of nuclear kappaB ligand (RANKL) pathway, which then promotes differentiation into osteoclasts, causing bone destruction.…”

A Tailored Approach for Appendicular Impending and Pathologic Fractures in Solid Cancer Metastases

“…Clinical studies are still ongoing [ 31 ]. Regarding the use of immunotherapy, a recent review by Liu et al explored the role of immunotherapy in common solid malignancies and the possible clinical application of immune checkpoint inhibitors in combination with RANKL inhibitors or the VEGFR inhibitor to counteract the immunosuppressive microenvironment in bone metastases and achieve better clinical outcomes [ 98 ]. With new medical approaches with targeted therapies and immunotherapy, survival is expected to improve along with quality of life in advanced disease.…”

The Stroma and Tumor Microenvironment Are Not the Most Instrumental Players in Tumor Cells Immune Evasion, Growth, and Resistance to Therapy

“…20 Bone TME is rich in immune cells, which are however unable to control the proliferation of primary or metastatic tumor cells, predominantly because of the paucity of T and natural killer (NK) cells. 28,29 The large numbers of regulatory T cells (Tregs) and MDSC are poised to impair the elusive antitumor activity of CD8+, CD4+, and NK cells, which are not expected in the first place to act against cancer cells that failed to express tumor specific antigens (TSA), HLA class I molecules, and NK cells-activating ligands. 4 Bone resident macrophages are dedicated to coordinating normal bone remodeling and injury repair rather than attacking tumor cells.…”

“…30 Accordingly, cancer-bone microenvironment provides an immune-privileged niche for tumor cells and contribute to the disease progression and to therapy resistance. [28][29][30][31] Cytotoxic T cells are unable to kill tumor cells that fail to express TSA-derived peptides in association with HLA class I molecules. Down modulation of surface membrane display of the latter license NK cells to action, providing activating molecules are not concealed due to biochemical changes in the cell membrane.…”