Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Shanghai 200031, China.
School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
EBioMedicine. 2017 Aug;22:58-67. doi: 10.1016/j.ebiom.2017.07.014. Epub 2017 Jul 18.
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.
肝细胞癌（HCC）是一种常见的消化道恶性肿瘤，治疗选择有限。虽然索拉非尼是一种口服多激酶抑制剂，可使晚期 HCC 患者获益，但由于个体差异和耐药性，临床效果有限。迫切需要将免疫疗法应用于 HCC。CCL2/CCR2 轴介导的巨噬细胞浸润是一种有前途的免疫治疗靶点。在这里，我们报告了一种来自乔治雪松的天然产物，命名为 747，其结构与山柰酚有关，作为 CCR2 拮抗剂具有敏感性和选择性。通过钙通量证明了 747 对 CCR2 的特异性，通过嵌合结合测定确定了 CCR2 的胞外环结合域，通过硫代乙醇酸盐诱导的腹膜炎模型证实了 747 的体内拮抗活性。在动物中，747 通过阻断肿瘤浸润巨噬细胞介导的免疫抑制作用增加肿瘤内 CD8+T 细胞的数量，并以 CD8+T 细胞依赖的方式抑制原位和皮下肿瘤生长。此外，747 在不增加明显毒性的情况下，通过增加肿瘤内 CD8+T 细胞的数量和增加肿瘤细胞的死亡，增强了低剂量索拉非尼的治疗效果。因此，我们发现了一种天然的 CCR2 拮抗剂，并为开发这种拮抗剂治疗 HCC 提供了新的视角。在 HCC 小鼠模型中，747 增强了肿瘤免疫抑制微环境，并增强了索拉非尼的治疗效果，表明免疫调节剂与化疗药物的联合应用可能是治疗 HCC 的一种新方法。
