1. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma.
- Author
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Li X, Yao W, Yuan Y, Chen P, Li B, Li J, Chu R, Song H, Xie D, Jiang X, and Wang H
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, Carcinoma, Hepatocellular drug therapy, Cell Communication, Cell Line, Tumor, Chemokine CCL2 genetics, Coculture Techniques, Disease Models, Animal, Gene Knockout Techniques, Humans, Liver Neoplasms drug therapy, Liver Neoplasms, Experimental drug therapy, Lymphocyte Activation drug effects, Lymphocyte Depletion, Lymphocytes, Tumor-Infiltrating drug effects, Mice, Prognosis, Receptors, CCR2 antagonists & inhibitors, Receptors, CCR2 genetics, Retrospective Studies, Signal Transduction drug effects, Tumor Escape, Tumor Microenvironment, Carcinoma, Hepatocellular immunology, Carcinoma, Hepatocellular metabolism, Chemokine CCL2 metabolism, Liver Neoplasms immunology, Liver Neoplasms metabolism, Liver Neoplasms, Experimental immunology, Liver Neoplasms, Experimental metabolism, Macrophages immunology, Neoplasm Recurrence, Local prevention & control, Receptors, CCR2 metabolism
- 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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)- Published
- 2017
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