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Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma
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Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma
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Journal Article
Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma
2017
Overview
ObjectiveHepatocellular 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.DesignCCL2 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.ResultCCL2 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.ConclusionsIn 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.
Publisher
BMJ Publishing Group LTD
Subject
/ Carcinoma, Hepatocellular - drug therapy
/ Carcinoma, Hepatocellular - immunology
/ Carcinoma, Hepatocellular - metabolism
/ CD8-Positive T-Lymphocytes - immunology
/ Humans
/ Liver Neoplasms - drug therapy
/ Liver Neoplasms - immunology
/ Liver Neoplasms - metabolism
/ Liver Neoplasms, Experimental - drug therapy
/ Liver Neoplasms, Experimental - immunology
/ Liver Neoplasms, Experimental - metabolism
/ Lymphocyte Activation - drug effects
/ Lymphocytes, Tumor-Infiltrating - drug effects
/ Mice
/ Neoplasm Recurrence, Local - prevention & control
/ Patients
/ Proteins
/ Receptors, CCR2 - antagonists & inhibitors
/ Receptors, CCR2 - metabolism
/ Signal Transduction - drug effects
/ Tumors
