title: Blocking the CCL2-CCR2 Axis Using CCL2-Neutralizing Antibody Is an Effective Therapy for Hepatocellular Cancer in a Mouse Model.
abstract: Hepatocellular carcinoma, a deadly disease, commonly arises in the setting of chronic inflammation. C-C motif chemokine ligand 2 (CCL2/MCP1), a chemokine that recruits CCR2-positive immune cells to promote inflammation, is highly upregulated in hepatocellular carcinoma patients. Here, we examined the therapeutic efficacy of CCL2-CCR2 axis inhibitors against hepatitis and hepatocellular carcinoma in the miR-122 knockout (a.k.a. KO) mouse model. This mouse model displays upregulation of hepatic CCL2 expression, which correlates with hepatitis that progress to hepatocellular carcinoma with age. Therapeutic potential of CCL2-CCR2 axis blockade was determined by treating KO mice with a CCL2-neutralizing antibody (nAb). This immunotherapy suppressed chronic liver inflammation in these mice by reducing the population of CD11highGr1+inflammatory myeloid cells and inhibiting expression of IL6 and TNFα in KO livers. Furthermore, treatment of tumor-bearing KO mice with CCL2 nAb for 8 weeks significantly reduced liver damage, hepatocellular carcinoma incidence, and tumor burden. Phospho-STAT3 (Y705) and c-MYC, the downstream targets of IL6, as well as NF-κB, the downstream target of TNFα, were downregulated upon CCL2 inhibition, which correlated with suppression of tumor growth. In addition, CCL2 nAb enhanced hepatic NK-cell cytotoxicity and IFNγ production, which is likely to contribute to the inhibition of tumorigenesis. Collectively, these results demonstrate that CCL2 immunotherapy could be an effective therapeutic approach against inflammatory liver disease and hepatocellular carcinoma. Mol Cancer Ther; 16(2); 312-22. ©2016 AACR.
authors.affiliation: Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, Ohio.|Department of Pathology, The Ohio State University, Columbus, Ohio.|Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio.
authors.forename: Kun-Yu
authors.initials: KY
authors.lastname: Teng
authors.affiliation: Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Han
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio.|Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio.
authors.forename: Shu-Hao
authors.initials: SH
authors.lastname: Hsu
authors.affiliation: Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio.|Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio.|Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shun
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio.|Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio.|Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio.
authors.forename: Nissar A
authors.initials: NA
authors.lastname: Wani
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio.|Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Barajas
authors.affiliation: Janssen Research and Development, LLC, Spring House, Pennsylvania.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Snyder
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio.|Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Frankel
authors.affiliation: Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio.|Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio.|Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio.|Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio.
authors.forename: Samson T
authors.initials: ST
authors.lastname: Jacob
authors.affiliation: Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio. kalpana.ghoshal@osumc.edu Jianhua.Yu@osumc.edu.|Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio. kalpana.ghoshal@osumc.edu Jianhua.Yu@osumc.edu.|Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio.|Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ghoshal
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008113:Liver Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D015415:Biomarkers; D018932:Chemokine CCL2; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D054390:Receptors, CCR2