Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23
Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23
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DOI：
10.1158/2159-8290.cd-19-0154
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发表时间：
2019-11-01
期刊：
影响因子：
28.2
通讯作者：
Thomas, David M.
中科院分区：
文献类型：
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作者：
Kansara, Maya;Thomson, Kristian;Thomas, David M.
谷氨酸代谢型受体 4 (GRM4) 位点通过未知的机制与人类骨肉瘤的易感性相关。我们发现 Grm4(-/-) 基因靶向小鼠表现出加速辐射诱导的肿瘤发展，其程度与 Rb1(+/-) 小鼠相当。 GRM4 在骨髓细胞中表达，选择性调节 IL23 和相关细胞因子 IL12 的表达。骨肉瘤条件培养基以GRM4依赖性方式诱导骨髓细胞Il23表达，同时抑制相关细胞因子Il12。人类和小鼠骨肉瘤均表达增加的 IL23:IL12 比率，而较高的 IL23 表达与人类较差的生存率相关。与致癌作用一致，Il23(-/-) 小鼠对骨肉瘤的发展具有显着的抵抗力。 GRM4 激动剂或 IL23 中和抗体可抑制小鼠骨肉瘤的生长。这些发现确定了一种新型的、可药物治疗的骨髓抑制途径，将 GRM4 与促炎性 IL23/IL12 轴联系起来。 意义：在过去的四十年中，很少出现针对骨肉瘤的新型全身疗法。利用从全基因组关联研究和小鼠模型中获得的见解，我们表明 GRM4 通过调节 IL23 的非细胞自主机制在驱动骨肉瘤中发挥作用，为治疗干预开辟了新途径。
The glutamate metabotropic receptor 4 (GRM4) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that Grm4(-/-) genetargeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with Rb1(+/-) mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion, while suppressing the related cytokine Il12. Both human and mouse osteosarcomas express an increased IL23:IL12 ratio, whereas higher IL23 expression is associated with worse survival in humans. Consistent with an oncogenic role, Il23(-/-) mice are strikingly resistant to osteosarcoma development. Agonists of GRM4 or a neutralizing antibody to IL23 suppressed osteosarcoma growth in mice. These findings identify a novel, druggable myeloid suppressor pathway linking GRM4 to the proinflammatory IL23/IL12 axis.SIGNIFICANCE: Few novel systemic therapies targeting osteosarcoma have emerged in the last four decades. Using insights gained from a genome-wide association study and mouse modeling, we show that GRM4 plays a role in driving osteosarcoma via a non-cell-autonomous mechanism regulating IL23, opening new avenues for therapeutic intervention.