title: Interactions between interleukin-6 and myeloid-derived suppressor cells drive the chemoresistant phenotype of hepatocellular cancer.
abstract: Emerging evidence implicates an important role for myeloid-derived suppressor cells (MDSCs) in tumor growth, angiogenesis and metastasis. However, limited knowledge is known about the function of MDSCs in response to chemotherapies. In this study, we find that drug-resistant hepatocellular cancer (HCC) cells-derived conditioned medium significantly enhances the expansion and immunosuppressive function of MDSCs compared to their parental sensitive cells, which is demonstrated by increased level of arginase, nitric oxide (NO), and reactive oxygen species (ROS). Next, we reveal that drug-resistant HCC cells-derived IL-6 activated MDSCs, which is demonstrated by using an anti-IL-6 neutralizing antibody that caused a reduced MDSC immunosuppressive activity. More importantly, the depletion of MDSC via the administration of anti-Gr-1 antibody or the blockade of IL-6 signaling sensitized 5-FU-resistant H22 hepatoma to chemotherapy in the immunocompetent C57BL/6N mice. In primary human HCC, IL-6 expression levels strongly correlate with an MDSC phenotype and chemotherapy response in HCC patients. In conclusion, these results describe a role of IL-6 in the drug resistance in HCC chemotherapy and suggest that MDSC-targeting treatments may be potential therapeutic strategy for HCC chemoresistance.
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
authors.forename: Xilin
authors.initials: X
authors.lastname: Lan
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
authors.forename: Siming
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
authors.forename: Minjiang
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
authors.forename: Zufei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
authors.forename: Weiqian
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
authors.forename: Fazong
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Tu
authors.affiliation: Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang, Lishui, Zhejiang 323000, PR China. Electronic address: lishuitumor@163.com.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Ji
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001119:Arginase / Q000235:genetics / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000093242:Interleukin-6 Inhibitors
chemical_list: D057134:Antibodies, Neutralizing; D000964:Antimetabolites, Antineoplastic; D001119:Arginase; D017077:Culture Media, Conditioned; D005472:Fluorouracil; D015850:Interleukin-6; D009569:Nitric Oxide; D017382:Reactive Oxygen Species; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human
keywords: Chemotherapy; Hepatocellular cancer; IL-6; MDSC