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Blocking the CCL2–CCR2 Axis Using CCL2 Published OnlineFirst December 15, 2016; DOI: 10.1158/1535-7163.MCT-16-0124 Large Molecule Therapeutics Molecular Cancer Therapeutics Blocking the CCL2–CCR2 Axis Using CCL2- Neutralizing Antibody Is an Effective Therapy for Hepatocellular Cancer in a Mouse Model Kun-Yu Teng1,2,3, Jianfeng Han3, Xiaoli Zhang4, Shu-Hao Hsu2,3, Shun He3,5,6, Nissar A. Wani2,3,8, Juan M. Barajas2,3, Linda A. Snyder7, Wendy L. Frankel2,3, Michael A. Caligiuri3,5, Samson T. Jacob3,5,8, Jianhua Yu3,5, and Kalpana Ghoshal2,3,8 Abstract þ Hepatocellular carcinoma, a deadly disease, commonly CD11highGr1 inflammatory myeloid cells and inhibiting arises in the setting of chronic inflammation. C-C motif chemo- expression of IL6 and TNFa in KO livers. Furthermore, treatment kine ligand 2 (CCL2/MCP1), a chemokine that recruits CCR2- of tumor-bearing KO mice with CCL2 nAb for 8 weeks signif- positive immune cells to promote inflammation, is highly upre- icantly reduced liver damage, hepatocellular carcinoma inci- gulated in hepatocellular carcinoma patients. Here, we exam- dence, and tumor burden. Phospho-STAT3 (Y705) and ined the therapeutic efficacy of CCL2–CCR2 axis inhibitors c-MYC, the downstream targets of IL6, as well as NF-kB, the against hepatitis and hepatocellular carcinoma in the miR- downstream target of TNFa, were downregulated upon CCL2 122 knockout (a.k.a. KO) mouse model. This mouse model inhibition, which correlated with suppression of tumor growth. displays upregulation of hepatic CCL2 expression, which corre- In addition, CCL2 nAb enhanced hepatic NK-cell cytotoxicity lates with hepatitis that progress to hepatocellular carcinoma and IFNg production, which is likely to contribute to the inhi- with age. Therapeutic potential of CCL2–CCR2 axis blockade bition of tumorigenesis. Collectively, these results demonstrate was determined by treating KO mice with a CCL2-neutralizing that CCL2 immunotherapy could be an effective therapeutic antibody (nAb). This immunotherapy suppressed chronic liver approach against inflammatory liver disease and hepatocellular inflammation in these mice by reducing the population of carcinoma. Mol Cancer Ther; 16(2); 312–22. Ó2016 AACR. Introduction infection in the past 20 years (3, 4). Furthermore, sorafenib, the only FDA-approved drug for advanced hepatocellular carcino- Hepatocellular carcinoma is the most common liver cancer ma extends overall survival by only 2.8 months (5). Recent and the second leading cause of cancer-related deaths world- clinical trials have shown that it is ineffective as an adjuvant wide (1, 2). The incidence of hepatocellular carcinoma has therapy after resection or ablation of the tumor (6). Thus, there tripled in the United States because of the precipitous increase is an urgent need to develop novel therapeutic strategies for the in nonalcoholic fatty liver disease and hepatitis C virus (HCV) treatment of hepatocellular carcinoma. miR-122 is the most abundant liver-specificmiRNAinverte- brates, and loss of miR-122 is associated with metastasis and 1Molecular, Cellular and Developmental Biology Program, The Ohio State Uni- poor prognosis in hepatocellular carcinoma patients (7). We versity, Columbus, Ohio. 2Department of Pathology, The Ohio State University, Columbus, Ohio. 3Comprehensive Cancer Center, Wexner Medical Center, The previously found that development of spontaneous hepatocel- Ohio State University, Columbus, Ohio. 4Center for Biostatistics, The Ohio State lular carcinoma with age mimicked different stages of tumor University, Columbus, Ohio. 5Virology, Immunology and Medical Genetics, The progression (e.g., steatohepatitis, fibrosis, primary, and meta- Ohio State University, Columbus, Ohio. 6Center for Systems Biology, Massachu- static hepatocellular carcinoma) in miR-122 knockout (KO) 7 setts General Hospital, Harvard Medical School, Boston, Massachusetts. Jans- mice (8, 9). We also observed that miR-122 depletion in the sen Research and Development, LLC, Spring House, Pennsylvania. 8Department mouse liver leads to upregulation of chemokine (C-C motif) of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, þ high þ Ohio. ligand 2 (CCL2), which recruits CCR2 CD11b Gr1 immune cells to the liver (8). These cells, in turn, produce Note: Supplementary data for this article are available at Molecular Cancer fl Therapeutics Online (http://mct.aacrjournals.org/). proin ammatory cytokines, including IL6 and TNFa in the liver, resulting in hepatitis and eventually hepatocellular carcinoma. K.-Y. Teng and J. Han contributed equally to this article. CCL2 is known to be involved in the pathogenesis of several Current address for Shun He: Massachusetts General Hospital (MGH), Harvard diseases characterized by monocytic infiltrates, such as psori- Medical School, Center for Systems Biology, Boston, MA. asis, rheumatoid arthritis, and atherosclerosis (10, 11). CCL2 Corresponding Authors: Kalpana Ghoshal, Department of Pathology, The Ohio also promotes local inflammation and macrophage infiltration State University, 420 West 12th Avenue, 646C TMRF Building, Columbus, OH in the chronically injured liver (12). Very recently, Li and 43210. Phone: 614-292-5688; Fax: 614-688-4245; E-mail: colleagues demonstrated that a chemical inhibitor of CCR2, [email protected]; and Jianhua Yu, [email protected] the receptor of CCL2, inhibited hepatocellular carcinoma doi: 10.1158/1535-7163.MCT-16-0124 development by reducing monocytes/macrophage infiltration þ Ó2016 American Association for Cancer Research. and M2 macrophage polarization as well as CD8 T-cell 312 Mol Cancer Ther; 16(2) February 2017 Downloaded from mct.aacrjournals.org on October 1, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst December 15, 2016; DOI: 10.1158/1535-7163.MCT-16-0124 CCL2 Immunotherapy Suppresses Hepatitis and HCC activation in the murine xenograft model (13). However, College of Medicine, Houston, TX). Although we did not whether targeting the CCL2–CCR2 axis by immunotherapy authenticate these cells, they exhibited characteristics and gene could be an effective therapeutic approach against chronic expression profile of mouse hepatoma cells. Hepa cells were inflammation and hepatocellular carcinoma has not been labeled with Chromium-51 (Cr-51) and then preincubated addressed. In this study, we addressed this important question with C1142 antibody or isotype antibody at a concentration using a novel preclinical model, miR-122 KO mice that develop of 10 mg/mL for 1 hour. Then, a standard 4-hour Cr-51 release chronic inflammation–driven hepatocellular carcinoma (8). assay (16) was performed to access cytotoxicity of mouse NK Our results clearly showed that targeting CCL2–CCR2 signaling cells against Hepa cells. by CCL2 immunotherapy could be an alternative approach in suppressing hepatitis and hepatocellular carcinoma develop- ELISA ment. Furthermore, our studies revealed that CCL2-neutraliz- For a-fetoprotein (AFP), mouse serum was collected by man- ing antibody (nAb) immunotherapy in miR-122 KO mouse dibular punch (before treatment) or cardiac punch (after treat- high þ fl model involves suppression of CD11b Gr1 in ammatory ment). KO mouse older than 10 months would be monitored for myeloid cell recruitment and enhancement of natural killer their body weight and serum AFP level by every 2 weeks. AFP level (NK) cell cytotoxicity. These observations underscore the was quantified by DRG AFP (Alpha Fetoprotein) Kit (DRG, cat# – importance of targeting CCL2 CCR2axisasapotentialtherapy EIA-1468). in a subset of human hepatocellular carcinoma patients with For IFNg, mouse liver mononuclear cells were isolated as fl chronic hepatic in ammation and high CCL2. described previously (8, 15). Hepa cells cultured in DMEM containing 10% FBS, were preincubated with C1142 (CCL2 Materials and Methods nAb) at a concentration of 10 mg/mL for 1 hour. Then, 106 Treatment of miR-122 KO mice with CCL2 antibody and CCR2 mononuclear cells were incubated with the same number of inhibitor Hepa cells per well in a 96-well V-bottom plate at 37 Cfor24 miR-122 KO mice were generated as described previously (8). hours. Culture supernatants were collected for IFNg estimation Animals were housed in Helicobacter-free facility under a 12-hour using mouse IFNg ELISA Ready-SET-Go Kit (eBioscience, cat# light/dark cycle. Animals were handled following the guidelines 88-7314-88). of the Ohio State University Institutional Laboratory Animal Care Committee. MRI CCL2 nAb (anti-mouse CCL2; clone C1142) was gener- MRI of liver tumors in miR-122 KO mice was performed as ously provided by Janssen (14). miR-122 KO mice were described previously (17). injected intraperitoneally with CCL2 nAb (2 mg/kg). The control group was injected with vehicle (PBS). To study the Serologic, histologic, and immunohistochemical analysis function of CCL2 in hepatitis, 4-month-old KO mice were Serum was isolated from mice by cardiac puncture after CO2 treated with CCL2 nAb twice a week for 4 weeks. To study asphyxiation and cervical dislocation and stored at À80C. Bio- the role of CCL2 in hepatocellular carcinoma development, chemical analysis of serum enzymes was performed using VetACE 12-month-oldKOmicewereinjectedwithCCL2nAbtwicea (Alfa Wassermann system) as described previously (8). Macro- week for 8 weeks. scopic tumors were counted, dissected, and weighed along with CCR2 inhibitor (Tocris Bioscience, cat# 2089) was given benign liver tissues. A fraction of tissues was fixed in 4% para- to KO mice in the drinking water daily (10 mg/kg)
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