Poster abstracts
Poster number 83 submitted by Kun-yu Teng
Blocking the Ccl2-Ccr2 axis using Ccl2 neutralizing antibody is an effective therapy for hepatocellular cancer in a mouse model
Kun-yu Teng (Department of Pathology), Jianfeng Han (3Comprehensive Cancer Center, Wexner Medical Center), Wendy L. Frankel (Department of Pathology), Michael A. Caligiuri (Virology, Immunology and Medical Genetics), Samson T. Jacob (Department of Molecular and Cellular Biochemistry,), Jianhua Yu (Virology, Immunology and Medical Genetics)
Abstract:
Hepatocellular carcinoma (HCC), a deadly disease, commonly arises in the setting of chronic inflammation. C-C motif chemokine ligand2 (CCL2/MCP1), a chemokine that recruits CCR2-positive immune cells to promote inflammation, is highly upregulated in HCC patients. Here, we examined the therapeutic efficacy of Ccl2-Ccr2 axis inhibitors in hepatitis and HCC using the miR-122 knockout (aka KO) mouse model. This mouse model displays upregulation of Ccl2, which correlates with liver inflammation and progresses to HCC with age. The therapeutic potential of blocking the Ccl2-Ccr2 axis was determined by treating KO mice with the Ccl2 neutralizing antibody (nab) and monitoring liver pathology. Ccl2 nab suppressed chronic hepatic inflammation in these mice by reducing the population of CD11highGr1+ inflammatory myeloid cells, and expression of IL-6 and TNF-a in KO livers. Furthermore, treatment of tumor-bearing KO mice with Ccl2 nab for 8 weeks significantly reduced recruitment of CD11bhighGr1+ cells, IL-6 and TNF-a production, liver damage and HCC incidence, as well as tumor burden. Downstream targets of IL-6, phospho-Stat3 (Y705), and c-Myc, as well as that of TNF-a NF-kB upon were down-regulated upon Ccl2 inhibition, and correlated with suppression of tumor growth. Additionally, enhanced cytotoxicity and IFN-g expression by natural killer (NK) cells isolated from the tumor microenvironment is likely to contribute tumorigenesis inhibition. In conclusion, our results demonstrate that Ccl2 immunotherapy could be effective against both inflammatory liver disease and HCC by modulating multiple pathways.
References:
Hsu SH, Wang B, Kota J, Yu J, Costinean S, Kutay H, et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. The Journal of clinical investigation. 2012;122:2871-83.
Keywords: Hepatocellular Carcinoma(HCC), microRNA-122 (miR-122), Immunotherapy