The IL-17-IL-17RA axis is required to promote osteosarcoma progression in mice

作者：Naoto Yoshimura, Ryusho Kariya, Masaki Shimada, Makoto Tateyama, Hideto Matsunaga, Yuto Shibata, Shuntaro Tanimura, Kosei Takata, Takahiro Arima, J. Kawakami, Kazuya Maeda, Yuko Fukuma, Masaru Uragami, Katsumasa Ideo, Kazuki Sugimoto, Ryuji Yonemitsu, Kozo Matsushita, Satoshi Hisanaga, Masaki Yugami, Yusuke Uehara, Tetsuro Masuda, Takayuki Nakamura, Takuya Tokunaga, Tatsuki Karasugi, Takanao Sueyoshi, Hiro Sato, Yoichiro Iwakura, Kimi Araki, Eisuke Kobayashi, Seiji Okada, Takeshi Miyamoto · 发表于：Scientific Reports · 年份：2023 · DOI：10.1038/s41598-023-49016-1 · 被引用次数：6 · 研究领域：Immunotherapy and Immune Responses、Cytokine Signaling Pathways and Interactions、Cancer Immunotherapy and Biomarkers

Osteosarcoma is rare but is the most common bone tumor. Diagnostic tools such as magnetic resonance imaging development of chemotherapeutic agents have increased the survival rate in osteosarcoma patients, although 5-year survival has plateaued at 70%. Thus, development of new treatment approaches is needed. Here, we report that IL-17, a proinflammatory cytokine, increases osteosarcoma mortality in a mouse model with AX osteosarcoma cells. AX cell transplantation into wild-type mice resulted in 100% mortality due to ectopic ossification and multi-organ metastasis. However, AX cell transplantation into IL-17-deficient mice significantly prolonged survival relative to controls. CD4-positive cells adjacent to osteosarcoma cells express IL-17, while osteosarcoma cells express the IL-17 receptor IL-17RA. Although AX cells can undergo osteoblast differentiation, as can patient osteosarcoma cells, IL-17 significantly inhibited that differentiation, indicating that IL-17 maintains AX cells in the undifferentiated state seen in malignant tumors. By contrast, IL-17RA-deficient mice transplanted with AX cells showed survival comparable to wild-type mice transplanted with AX cells. Biopsy specimens collected from osteosarcoma patients showed higher expression of IL-17RA compared to IL-17. These findings suggest that IL-17 is essential to maintain osteosarcoma cells in an undifferentiated state and could be a therapeutic target for suppressing tumorigenesis.