• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>EBioMedicine >A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer
【24h】

A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer

机译：天然CCR2拮抗剂可减轻肿瘤相关巨噬细胞介导的免疫抑制，从而产生治疗肝癌的作用

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Hepatocellular carcinoma (HCC) is a common malignant tumor in the digestive tract with limited therapeutic choices. Although sorafenib, an orally administered multikinase inhibitor, has produced survival benefits for patients with advanced HCC, favorable clinical outcomes are limited due to individual differences and resistance. The application of immunotherapy, a promising approach for HCC is urgently needed. Macrophage infiltration, mediated by the CCL2/CCR2 axis, is a potential immunotherapeutic target. Here, we report that a natural product from Abies georgei, named 747 and related in structure to kaempferol, exhibits sensitivity and selectivity as a CCR2 antagonist. The specificity of 747 on CCR2 was demonstrated via calcium flux, the binding domain of CCR2 was identified in an extracellular loop by chimera binding assay, and in vivo antagonistic activity of 747 was confirmed through a thioglycollate-induced peritonitis model. In animals, 747 elevated the number of CD8+ T cells in tumors via blocking tumor-infiltrating macrophage-mediated immunosuppression and inhibited orthotopic and subcutaneous tumor growth in a CD8+ T cell-dependent manner. Further, 747 enhanced the therapeutic efficacy of low-dose sorafenib without obvious toxicity, through elevating the numbers of intra-tumoral CD8+ T cells and increasing death of tumor cells. Thus, we have discovered a natural CCR2 antagonist and have provided a new perspective on development of this antagonist for treatment of HCC. In mouse models of HCC, 747 enhanced the tumor immunosuppressive microenvironment and potentiated the therapeutic effect of sorafenib, indicating that the combination of an immunomodulator with a chemotherapeutic drug could be a new approach for treating HCC.
机译：肝细胞癌（HCC）是消化道中常见的恶性肿瘤，治疗选择有限。尽管口服多激酶抑制剂索拉非尼对晚期肝癌患者具有生存优势，但由于个体差异和耐药性，临床效果有限。迫切需要免疫疗法的应用，这是一种有希望的肝癌治疗方法。由CCL2 / CCR2轴介导的巨噬细胞浸润是潜在的免疫治疗靶标。在这里，我们报告说，来自Abies georgei的天然产物，名为747，在结构上与山奈酚有关，表现出作为CCR2拮抗剂的敏感性和选择性。通过钙通量证明747对CCR2的特异性，通过嵌合体结合测定法在细胞外环中鉴定出CCR2的结合结构域，并通过巯基乙酸盐诱导的腹膜炎模型证实747的体内拮抗活性。在动物中，747通过阻断肿瘤浸润性巨噬细胞介导的免疫抑制而升高了肿瘤中CD8 + T细胞的数量，并以CD8 ​​+ T细胞依赖性的方式抑制了原位和皮下肿瘤的生长。此外，747通过增加肿瘤内CD8 + T细胞的数量并增加肿瘤细胞的死亡，增强了低剂量索拉非尼的治疗效果，而没有明显的毒性。因此，我们发现了一种天然的CCR2拮抗剂，并为该拮抗剂治疗肝癌的发展提供了新的视角。在肝癌的小鼠模型中，747增强了肿瘤的免疫抑制微环境，并增强了索拉非尼的治疗效果，这表明免疫调节剂与化学治疗药物的结合可能是治疗肝癌的一种新方法。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号