title: Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yao
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Peizhan
authors.initials: P
authors.lastname: Chen
authors.affiliation: The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.
authors.forename: Jingquan
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ruiai
authors.initials: R
authors.lastname: Chu
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Song
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.|School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Xie
authors.affiliation: The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.|School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D002450:Cell Communication; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D011379:Prognosis; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects; D019139:Tumor Escape; D059016:Tumor Microenvironment
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2
keywords: CELL BIOLOGY; CHEMOKINES; HEPATOCELLULAR CARCINOMA; IMMUNOLOGY IN HEPATOLOGY; MACROPHAGES