Immunotherapy as a potential treatment approach for currently incurable bone metastasis

Abstract

Once cancer metastasizes to the bone, the prognosis of cancer patients becomes extremely poor. Unfortunately, the current most successful treatment for bone metastasis can extend their survival by only a few months. Although recent studies have revealed promising impacts of cancer immunotherapies, their treatment efficacy on bone metastatic diseases remains controversial. Therefore, in this review, we discussed (i) preclinical and clinical evidence of the immunotherapeutic strategies for cancer bone metastasis, mainly focusing on cell-based immunotherapy, cytokine-based immunotherapy, and immune checkpoint blockade, and (ii) current shortcomings of immunotherapy for bone metastasis and their potential future directions. Although the evidence on treatment efficacy and safety, as well as long-term effects, is limited, immunotherapies could induce partial or complete remissions in a few cancer patients with bone metastasis. However, there are still hurdles, such as the immunosuppressive nature of the bone marrow microenvironment and poor distribution of cell-based immunotherapies to bone, that need to be overcome to enhance the treatment efficacy of immunotherapies on bone metastasis. While it is apparent that further investigation is needed regarding immunotherapeutic treatment efficacy in patients with bone metastasis, this therapy may prove to be clinically novel in this subset of cancer patients.

Keywords: Bone metastasis; Bone microenvironment; Cell-based immunotherapies; Immune checkpoint blockade; Immunotherapy.

Fig. 1

Models of specific immune evasion in bone metastasis and the potential therapeutic strategies. As shown in the left panel, when bone metastatic cancer cells interact with osteoclasts in the bone marrow, these cancer-associated osteoclasts mediate bone resorption, in which the resorbed bone releases transforming growth factor-beta (TGF-β). TGF-β released from bone is known to inhibit the differentiation of CD4 T cells (CD4 T) into T helper 1 cells (Th1). Additionally, bone marrow mesenchymal stem cells (MSCs) prevent the secretion of interferon-gamma (IFN-γ, a cytokine known to suppress tumor growth) from CD8 T cells (CD8 T) (based on in vitro studies). These bone marrow-specific mechanisms allow bone metastatic cancer cells to evade the immune system, which contributes to the limited treatment efficacy of immunotherapy for bone metastasis. Conversely, as shown in the right panel, TGF-β that was released from the bone can be blocked with anti-TGF-β antibodies, which allows CD4 T cells to differentiate into Th1 cells. By releasing cytokines, Th1 cells are then able to support CD8 T cells to kill tumor cells. Further, treatment with an indoleamine 2,3-dioxygenase (IDO1) inhibitor, 1-methyl-l-tryptophan (1-l-MT) can prevent the MSC-mediated inhibition of IFN-γ release from T cells (based on in vitro studies). Through activation of CD8 T cells and IFN-γ release, cytotoxicity to bone metastatic cancer cells can be increased, thus enhancing immune response in the bone marrow microenvironment. We propose that by enhancing CD8 T cell tumor-killing ability through anti-TGF-β antibody and 1-l-MT treatment, efficacy of immunotherapies for bone metastatic disease may be improved