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.
- CELL BIOLOGY
- HEPATOCELLULAR CARCINOMA
- IMMUNOLOGY IN HEPATOLOGY
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Correction notice This article has been corrected since it published Online First. The funding statement has been updated.
Acknowledgements The authors thank Dr Donald L Hill for editorial assistance.
Contributors XL and HW conceived and designed experiments. XL and HW analysed data and wrote the manuscript. HW supervised the project. XL, WY, YY, PC and JL performed the in vitro and in vivo studies. Pathology support, tissue provision and patients' information collection were accomplished by BL and XJ. RC, HS and DX assisted in experimental design and data evaluation. All authors reviewed and approved the manuscript.
Funding This work was supported by grants from the Ministry of Science and Technology of China (2014AA020524), the National Natural Science Foundation of China (91529305, 81125020, 81427805, 81302809 and 81502122), the Instrument Developing Project of the Chinese Academy of Sciences, the Science and Technology Commission of Shanghai Municipality (12431900500 and 14391901800), the China Postdoctoral Science Foundation (2014M551469), the CAS-SIBS Postdoctoral Foundation (2014KIP315), and the Key Laboratory of Food Safety Research of INS, SIBS, CAS.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Internal Review and Ethics Boards of the Shanghai Eastern Hepatobiliary Surgery Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.