Immune Checkpoint Inhibitor Therapy for Bone Metastases: Specific Microenvironment and Current Situation (1)
The immune checkpoints, such as programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA- 4), are the most important signal molecules that mediate the immune escape of tumors. The immune checkpoint inhibitors (ICIs) can block the above-mentioned signals that help tumor’s immune escape so that the immune response would be reactivated and the tumors would be killed by the patient’s immune system.
As an immune organ, bone has a different immune microenvironment from other organs, which makes bone metastases different from the primary tumor and other metastases. In humans and mice, monocytes in peripheral blood are composed of 45-75% of T lymphocytes, including 25-60% of CD4+ and 5-30% of CD8+ T cells. However, in the bone marrow, the proportion of T cells decreased to less than 5% of monocytes, and CD8+ T cells were more abundant than CD4+ T cells. Similar to T cells, natural killer (NK) cells make up only 1-2% of lymphocytes in the bone marrow, although bone is the main site of their development.
Osteoblasts and osteoclasts in bone are key components of bone homeostasis. Most of the factors involved in the differentiation of osteoclasts and preosteoclasts come from the immune system, such as macrophage colony stimulating factor (M-CSF), interleukin (IL), transforming growth factor-β (TFG-β), prostaglandins, and interferon-γ (IFN-γ).
Th17 can induce the expression of M-CSF and RANKL (receptor activator of nuclear factor-kB ligand) in osteoblasts and stromal cells, produce RANKL and tumor necrosis factor-α (TNF-α), and simultaneously increase the expression of RANK in osteoclast precursors osteoclasts also have immunomodulatory effects. The osteoclasts can present antigens, inhibit T cell initiation or proliferation, induce T cell incompetence, and express immunosuppressive and/or tolerable factors such as cytokines (including IL-10) and metabolic enzymes indoleamine 2,3-dioxygenase 1 (IDO1, which breaks down and depletes tryptophan, thus limiting T cell local activity). For osteoblasts, although there are few immune-related studies at present, a large number of immune factors are found to be involved in their generation and regulation. Meanwhile, osteoblasts, perivascular stromal cells, and endothelial cells are also components of the hematopoietic stem cell (HSC) niche and regulate the maintenance of HSC.
Tumor cells release cytokines, which break the balance between osteo- blasts and osteoclasts, to cause bone destruction and create an immunosuppressive microenvironment, thus promoting tumor progression and forming a “vicious cycle”.
The CTLA-4 inhibitor ipilimumab monotherapy did not induce an antitumor response in the model because of the deficiency of Th1 cell in the microenvironment. Under the combined effect of TGF-β and IL-6 in the bone marrow, CD4+ T cells polarize to the Th17 cells rather than Th1 effector cells. Simultaneously blocking TGF-β and CTLA-4 increased the number of CD4+ helper T cells in tumors, especially Th1 effector cells, leading to a significant increase in clonal amplification of CD8+ T cell and a decrease of Treg cells. The combination therapy significantly inhibited the progression of bone metastases and improved overall survival.
The PD-1 level of exosomes derived from DC and T lymphocytes can be used to predict overall and progression-free survival in melanoma populations. In a femoral metastasis model, PD-L1 and chemokine (C-C motif) ligand 2 (CCl2) were upregulated, and PD-L1 induced osteoclastogenesis.
Cancer-associated fibroblasts (CAFs) are fibro- blasts that accumulate in tumors. The CAFs can form an immunosuppressive microenvironment through a variety of mechanisms (including upregulating the PD-1 expression of immune cells), which would promote tumor proliferation, cause tumor immune escape, and mediate drug resistance.
There are a relatively large number of immature or suppressive immune cells in the bone, which makes bone a site with low immune function. As bone metastases are more heterogeneous than primary tumors and metastases in other organs, it may not be possible to predict the therapeutic effects of ICIs by the expression of PD-L1 alone. Resistance to ICIs has been described, including primary resistance and acquired resistance. Primary resistance refers to those cases in which no initial response to immune checkpoint inhibitor was observed.