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.
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发表于 2015-11-3 14:32