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Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma
  1. Xiaoguang Li1,
  2. Wenbo Yao1,
  3. Ya Yuan1,
  4. Peizhan Chen1,
  5. Bin Li2,
  6. Jingquan Li1,3,
  7. Ruiai Chu1,
  8. Haiyun Song1,3,
  9. Dong Xie1,3,4,
  10. Xiaoqing Jiang2,
  11. Hui Wang1,3,4
  1. 1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
  2. 2The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
  3. 3Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China
  4. 4School of Life Science and Technology, Shanghai Tech University, Shanghai, China
  1. Correspondence to Professor Hui Wang, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 YueYang Road, Shanghai 200031, China; huiwang{at}sibs.ac.cn

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.

  • MACROPHAGES
  • CELL BIOLOGY
  • CHEMOKINES
  • HEPATOCELLULAR CARCINOMA
  • IMMUNOLOGY IN HEPATOLOGY

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