title: Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes.
abstract: Chronic inflammation in liver tissue is an underlying cause of hepatocellular carcinoma. High levels of inflammatory cytokine IL18 in the circulation of patients with hepatocellular carcinoma correlates with poor prognosis. However, conflicting results have been reported for IL18 in hepatocellular carcinoma development and progression. In this study, we used tissue specimens from hepatocellular carcinoma patients and clinically relevant mouse models of hepatocellular carcinoma to evaluate IL18 expression and function. In a mouse model of liver fibrosis that recapitulates a tumor-promoting microenvironment, global deletion of the IL18 receptor IL18R1 enhanced tumor growth and burden. Similarly, in a carcinogen-induced model of liver tumorigenesis, IL18R1 deletion increased tumor burden. Mechanistically, we found that IL18 exerted inflammation-dependent tumor-suppressive effects largely by promoting the differentiation, activity, and survival of tumor-infiltrating T cells. Finally, differences in the expression of IL18 in tumor tissue versus nontumor tissue were more predictive of patient outcome than overall tissue expression. Taken together, our findings resolve a long-standing contradiction regarding a tumor-suppressive role for IL18 in established hepatocellular carcinoma and provide a mechanistic explanation for the complex relationship between its expression pattern and hepatocellular carcinoma prognosis. Cancer Res; 76(8); 2394-405. ©2016 AACR.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Markowitz
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina. Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. National Center for Liver Cancer, Second Military Medical University, Shanghai, China.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Yang
authors.affiliation: National Center for Liver Cancer, Second Military Medical University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Gastroenterology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Michelotti
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Biologics Research Center, National Institute of Biological Sciences, Beijing, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Sui
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: National Center for Liver Cancer, Second Military Medical University, Shanghai, China.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Qin
authors.affiliation: Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China.
authors.forename: Fu-Sheng
authors.initials: FS
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
authors.affiliation: National Center for Liver Cancer, Second Military Medical University, Shanghai, China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina. wang0011@mc.duke.edu.
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011379:Prognosis; D053724:Receptors, Interleukin-18 / Q000235:genetics; D015398:Signal Transduction
chemical_list: D020382:Interleukin-18; D053724:Receptors, Interleukin-18