Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma
Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma
复制标题
通过 CCL2/CCR2 信号传导靶向肿瘤浸润巨噬细胞作为肝细胞癌的治疗策略
DOI：
10.1136/gutjnl-2015-310514
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发表时间：
2017-01-01
期刊：
影响因子：
24.5
通讯作者：
Wang, Hui
中科院分区：
文献类型：
--
作者：
Li, Xiaoguang;Yao, Wenbo;Wang, Hui
目的肝细胞癌是一种侵袭性较强的恶性肿瘤，有效的治疗方法有限。另一种策略是针对肝癌肿瘤微环境中的细胞，如肿瘤浸润性巨噬细胞。CCL2/CCR2轴是单核/巨噬细胞募集所必需的，与肝脏病理的各个方面有关，包括肝细胞癌。我们研究了CCL2/CCR2作为抗肝癌治疗靶点的可行性。设计CCL2在两个独立的肝癌队列中的表达被分析。用新型CCR2拮抗剂阻断CCL2/CCR2轴或敲除宿主CCR2后，在原位模型、术后复发模型和皮下模型中评价了三种小鼠肝癌细胞的生长情况。体内巨噬细胞或T细胞去除和体外细胞共培养进一步研究CCL2/CCR2介导的肿瘤相关巨噬细胞(TAMs)与肿瘤细胞之间的串扰。结果CCL2在人肝癌组织中高表达，对肝细胞癌患者的预后有预测作用。通过敲除CCR2或使用CCR2拮抗剂阻断CCL2/CCR2信号通路可以抑制肿瘤的生长和转移，减少术后复发，提高生存率。此外，治疗性阻断CCL2/CCR2轴可抑制炎性单核细胞的募集、TAMs的渗透和M2极化，从而逆转肿瘤微环境的免疫抑制状态，并激活抗肿瘤CD8+T细胞反应。结论CCL2在肝癌组织中呈高表达，可作为判断预后的指标。阻断CCL2/CCR2信号通过激活T细胞抗肿瘤免疫反应抑制小鼠肝癌生长。这些结果证明了CCL2/CCR2阻断剂治疗肝癌的翻译潜力。
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.