Abstract
Advanced, recurrent, or metastasized osteosarcomas remain challenging to cure or even alleviate. Therefore, the development of novel therapeutic strategies is urgently needed. Cancer immunotherapy has greatly improved in recent years, with options including adoptive cellular therapy, vaccination, and checkpoint inhibitors. As such, immunotherapy is becoming a potential strategy for the treatment of osteosarcoma. Innate immunocytes, the first line of defense in the immune system and the bridge to adaptive immunity, are one of the vital effector cell subpopulations in cancer immunotherapy. Innate immune cell-based therapy has shown potent antitumor activity against hematologic malignancies and some solid tumors, including osteosarcoma. Importantly, some immune checkpoints are expressed on both innate and adaptive immune cells, modulating their functions in tumor immunity. Therefore, blocking or activating immune checkpoint-mediated downstream signaling pathways can improve the therapeutic effects of innate immune cell-based therapy. In this review, we summarize the current status and future prospects of innate immune cell-based therapy for the treatment of osteosarcoma, with a focus on the potential synergistic effects of combination therapy involving innate immunotherapy and immune checkpoint inhibitors/oncolytic viruses.
Highlights
Osteosarcoma is the most common primary malignant bone tumor and it often leads to pulmonary metastasis, which is the major cause of death of osteosarcoma patients [1]
We describe the anti-osteosarcoma roles of the following major classes of innate immune cells: dendritic cells (DCs), macrophages, natural killer (NK) cells, natural killer T cells (NKT) cells, and γδ T cells
We found that VPA and ZOL had a synergistic effect on the enhancement of γδ T cell-mediated cytotoxicity against osteosarcoma cells by facilitating the accumulation of mevalonate pathway intermediates [11]
Summary
Osteosarcoma is the most common primary malignant bone tumor and it often leads to pulmonary metastasis, which is the major cause of death of osteosarcoma patients [1]. There are three ancillary strategies to further improve the therapeutic effectiveness of adoptive NK cell transfer in osteosarcoma immunotherapy (Table 3) Epigenetic drugs, such as histone deacetylase inhibitors (HDACi, e.g., valproic acid [VPA], entinostat) and DNA-methylation inhibitors (DNMTi, e.g., hydralazine) can increase the expression of ligands for activating receptors (MICA/B, ULBP, and CD155) or death receptors (Fas) on osteosarcoma cells, enhancing NK cell-mediated lysis [62, 63, 65]. We found that VPA (the HDACi) and ZOL had a synergistic effect on the enhancement of γδ T cell-mediated cytotoxicity against osteosarcoma cells by facilitating the accumulation of mevalonate pathway intermediates [11] This combination therapy reduced the ZOL dose required in adoptive γδ T cell transfer immunotherapy, facilitating its clinical application [11].
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