title: Amphiregulin activates regulatory T lymphocytes and suppresses CD8+ T cell-mediated anti-tumor response in hepatocellular carcinoma cells.
abstract: CD8+ T cell-mediated immune response plays an important role in inhibiting progression of hepatocellular carcinoma (HCC). For strategic immunotherapy, it is critical to understand why some of the tumor cells escape from this immune attack. In this study, we investigated how HCC cells alter endogenous anti-tumor immunity and their related signaling pathways. We found that HCC cells, both in vitro and in vivo, substantially secret and express amphiregulin (AR). AR in turn activates immunosuppressive function of intratumoral CD4+Foxp3+ regulatory T cells (Tregs), a major inhibitor of CD8+ T cells. Using either lentiviral siRNA, or AR neutralizing antibody, we blocked the expression and function of AR to test the specificity of AR mediated activation of Tregs, Biochemical and cell biology studies were followed and confirmed that blocking of AR inhibited Tregs activation. In addition, we found that AR can trigger the activation of rapamycin complex 1(mTORC1) signaling in Tregs. The mTORC1 inhibitor rapamycin treatment led to compromise Treg function and resulted in enhancing anti-tumor function of CD8+ T cells. Blocking AR/EGFR signaling in Tregs with Gefitinib also enhanced anti-tumor immunity and decreased tumor size in a mouse xenograft tumor model. Taken together, our study suggested a novel mechanism of functional interaction between HCC and Tregs for regulating anti-tumor function of CD8+ T cells.
authors.affiliation: Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Yuan
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Sun
authors.affiliation: The State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuchang District, Wuhan 430072, P.R. China.
authors.forename: Cheng-Liang
authors.initials: CL
authors.lastname: Zhu
authors.affiliation: Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Shao-Ping
authors.initials: SP
authors.lastname: Liu
authors.affiliation: Department of Oncology, Renmin Hospital of Wuhan University, Wuchang District, Wuhan 430060, P.R. China.
authors.forename: Long
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Oncology, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Mao-Hui
authors.initials: MH
authors.lastname: Feng
authors.affiliation: Animal Experiment Center of Wuhan University/Animal Biosafety Level-III Laboratory, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
authors.forename: Fu-Bing
authors.initials: FB
authors.lastname: Wang
mesh_terms: D066258:Amphiregulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D066258:Amphiregulin; D012333:RNA, Messenger; D034741:RNA, Small Interfering
keywords: CD4+ regulatory T cells; CD8+ T cells; amphiregulin; hepatocellular carcinoma