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| A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer | |
| 2017-08 | |
| 发表期刊 | EBIOMEDICINE
 |
| ISSN | 2352-3964 |
| 卷号 | 22页码:58-67 |
| 发表状态 | 已发表 |
| DOI | 10.1016/j.ebiom.2017.07.014 |
| 摘要 | Hepatocellular carcinoma (HCC) is a common malignant tumor in the digestive tract with limited therapeutic choices. Although sorafenib, an orally administeredmultikinase 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 CCR2was demonstrated via calciumflux, 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-dependentmanner. Further, 747 enhanced the therapeutic efficacy of low-dose sorafenibwithout 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. Inmousemodels ofHCC, 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. (C) 2017 The Authors. Published by Elsevier B.V. |
| 关键词 | Preclinical models Combination therapy Experimental therapeutics Kaempferol Immunotherapy |
| 收录类别 | SCI |
| 语种 | 英语 |
| 资助项目 | Science and Technology Commission of Shanghai Municipality[16391903700] ; Science and Technology Commission of Shanghai Municipality[14391901800] |
| WOS研究方向 | General & Internal Medicine ; Research & Experimental Medicine |
| WOS类目 | Medicine, General & Internal ; Medicine, Research & Experimental |
| WOS记录号 | WOS:000410738600011 |
| 出版者 | ELSEVIER SCIENCE BV |
| WOS关键词 | ADVANCED HEPATOCELLULAR-CARCINOMA ; CHEMOKINE RECEPTOR ; IMMUNOTHERAPY ; PROTEIN ; SORAFENIB ; INHIBITION ; RESISTANCE ; FUTURE ; MICE ; CCL2 |
| 原始文献类型 | Article |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/4648 |
| 专题 | 物质科学与技术学院 生命科学与技术学院 生命科学与技术学院_特聘教授组_王慧组 生命科学与技术学院_硕士生 生命科学与技术学院_博士生 |
| 通讯作者 | Zhang, Weidong; Wang, Hui |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Food Safety Res, Shanghai 200031, Peoples R China 2.Shanghai Jiao Tong Univ, Sch Publ Hlth, Sch Med, Shanghai 200025, Peoples R China 3.Second Mil Med Univ, Sch Pharm, Dept Phytochem, Rm 1106,1 Bldg,325 GuoHe Rd, Shanghai 200433, Peoples R China 4.East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China 6.Univ Chinese Acad Sci, Shanghai 200031, Peoples R China |
| 通讯作者单位 | 生命科学与技术学院 |
| 推荐引用方式 GB/T 7714 | Yao, Wenbo,Ba, Qian,Li, Xiaoguang,et al. A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer[J]. EBIOMEDICINE,2017,22:58-67. |
| APA | Yao, Wenbo.,Ba, Qian.,Li, Xiaoguang.,Li, Huiliang.,Zhang, Shoude.,...&Wang, Hui.(2017).A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer.EBIOMEDICINE,22,58-67. |
| MLA | Yao, Wenbo,et al."A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer".EBIOMEDICINE 22(2017):58-67. |
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