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标题: 通过CCL2 / CCR2信号靶向肿瘤浸润的巨噬细胞对抗肝癌的治疗策 [打印本页]
作者: StephenW 时间: 2015-11-3 14:32 标题: 通过CCL2 / CCR2信号靶向肿瘤浸润的巨噬细胞对抗肝癌的治疗策
Gut doi:10.1136/gutjnl-2015-310514
Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma - Xiaoguang Li1,
- Wenbo Yao1,
- Ya Yuan1,
- Peizhan Chen1,
- Bin Li2,
- Jingquan Li1,3,
- Ruiai Chu1,
- Haiyun Song1,3,
- Dong Xie1,3,4,
- Xiaoqing Jiang2,
- Hui Wang1,3,4
- Author Affiliations
- 1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
- 2The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- 3Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China
- 4School of Life Science and Technology, Shanghai Tech University, Shanghai, China
- Correspondence to Professor Hui Wang, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 YueYang Road, Shanghai 200031, China; [email protected]
- Received 6 August 2015
- Revised 2 September 2015
- Accepted 14 September 2015
- Published Online First 9 October 2015
Abstract Objective Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. An alternative strategy is to target cells, such as tumour-infiltrating macrophages, in the HCC tumour microenvironment. The CCL2/CCR2 axis is required for recruitment of monocytes/macrophages and is implicated in various aspects of liver pathology, including HCC. We investigated the feasibility of CCL2/CCR2 as a therapeutic target against HCC.
Design CCL2 expression was analysed in two independent HCC cohorts. Growth of three murine HCC cells was evaluated in an orthotopic model, a postsurgical recurrence model and a subcutaneous model in mice after blocking CCL2/CCR2 axis by a novel CCR2 antagonist or knocking out of host CCR2. In vivo macrophage or T cell depletion and in vitro cell coculture were further conducted to investigate CCL2/CCR2-mediated crosstalk between tumour-associated macrophages (TAMs) and tumour cells.
Result CCL2 is overexpressed in human liver cancers and is prognostic for patients with HCC. Blockade of CCL2/CCR2 signalling with knockout of CCR2 or with a CCR2 antagonist inhibits malignant growth and metastasis, reduces postsurgical recurrence, and enhances survival. Further, therapeutic blocking of the CCL2/CCR2 axis inhibits the recruitment of inflammatory monocytes, infiltration and M2-polarisation of TAMs, resulting in reversal of the immunosuppression status of the tumour microenvironment and activation of an antitumorous CD8+ T cell response.
Conclusions In patients with liver cancer, CCL2 is highly expressed and is a prognostic factor. Blockade of CCL2/CCR2 signalling suppresses murine liver tumour growth via activating T cell antitumour immune response. The results demonstrate the translational potential of CCL2/CCR2 blockade for treatment of HCCs.
作者: StephenW 时间: 2015-11-3 14:32
肠道DOI:10.1136 / gutjnl-2015-310514
肝病
原创文章
通过CCL2 / CCR2信号靶向肿瘤浸润的巨噬细胞对抗肝癌的治疗策略
晓光丽1,文博Yao1,雅媛,Peizhan臣1,宾力2,井圈Li1,3,瑞霭Chu1,海云Song1,3,董Xie1,3,4,小青Jiang2,惠Wang1,3,4
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作者机构
食品安全研究所营养科学,上海生命科学研究院,中国院士,上海,中国实验室重点开放,
2The东方肝胆外科医院,第二军医大学,上海,中国
食品安全风险评估,卫生部,中国北京3Key实验室
生命科学与技术,上海理工大学,上海,中国的学校工程
通讯作者王辉教授,研究院营养科学,上海生命科学研究院,中国院士,岳阳路320号,上海200031,中国; [email protected]
收到的2015年6月
修订2 2015年九月
接受2015年14月
网上公布首9 2015年10月
抽象的
客观肝细胞癌(HCC)是有限的有效的治疗方案的侵略性的恶性肿瘤。一种替代的策略是对靶细胞,如肿瘤浸润巨噬细胞,在肝癌肿瘤微环境。的CCL2 / CCR2轴需要招募单核细胞/巨噬细胞和牵连在肝脏病理的各个方面,包括肝癌。我们调查了CCL2 / CCR2的可行性,对肝癌的治疗靶点。
设计CCL2表达在两个独立的肝癌组群分析。小鼠3种肝癌细胞生长的原位模型中,术后复发模型和小鼠皮下模型阻断CCL2 / CCR2轴的一种新的CCR2拮抗或敲除主机CCR2的后评价。体内的巨噬细胞或T细胞耗竭和体外细胞共培养,进一步进行研究的肿瘤相关巨噬细胞(噬细胞)和肿瘤细胞之间的CCL2 / CCR2介导的串扰。
结果CCL2过度表达在人类肝癌,是预后的肝癌患者。 CCL2 / CCR2与CCR2的或具有CCR2拮抗剂敲除信令的阻断抑制恶性肿瘤的生长和转移,降低手术后复发,和增强的存活。此外,CCL2 / CCR2轴的治疗性阻断抑制炎性单核细胞,浸润和M2偏振噬细胞的招募,产生反转的antitumorous CD8 + T细胞应答的肿瘤微环境和活化的免疫抑制状态。
结论肝癌患者,CCL2高度表达,是一个预后因素。 CCL2 / CCR2信号的阻断通过激活T细胞抗肿瘤的免疫反应抑制小鼠肝癌的肿瘤生长。结果证明CCL2 / CCR2阻断治疗肝癌的转化潜力。
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