title: USP18 is crucial for IFN-γ-mediated inhibition of B16 melanoma tumorigenesis and antitumor immunity.
abstract: BACKGROUND
  Interferon (IFN)-γ-mediated immune response plays an important role in tumor immunosurveillance. However, the regulation of IFN-γ-mediated tumorigenesis and immune response remains elusive. USP18, an interferon stimulating response element, regulates IFN-α-mediated signaling in anti-viral immune response, but its role in IFN-γ-mediated tumorigenesis and anti-tumor immune response is unknown.
  
  
  METHODS
  In this study, USP18 in tumorigenesis and anti-tumor immune response was comprehensively appraised in vivo by overexpression or downregulation its expression in murine B16 melanoma tumor model in immunocompetent and immunodeficient mice.
  
  
  RESULTS
  Ectopic expression or downregulation of USP18 in B16 melanoma tumor cells inhibited or promoted tumorigenesis, respectively, in immunocompetent mice. USP18 expression in B16 melanoma tumor cells regulated IFN-γ-mediated immunoediting, including upregulating MHC class-I expression, reducing tumor cell-mediated inhibition of T cell proliferation and activation, and suppressing PD-1 expression in CD4+ and CD8+ T cells in tumor-bearing mice. USP18 expression in B16 melanoma tumor cells also enhanced CTL activity during adoptive immunotherapy by prolonging the persistence and enhancing the activity of adoptively transferred CTLs and by reducing CTL exhaustion in the tumor microenvironment. Mechanistic studies demonstrated that USP18 suppressed tumor cell-mediated immune inhibition by activating T cells, inhibiting T-cell exhaustion, and reducing dendritic cell tolerance, thus sensitizing tumor cells to immunosurveillance and immunotherapy.
  
  
  CONCLUSIONS
  These findings suggest that stimulating USP18 is a feasible approach to induce B16 melanoma specific immune response.
authors.forename: Bangxing
authors.initials: B
authors.lastname: Hong
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Lu
authors.forename: Mingjun
authors.initials: M
authors.lastname: Zhang
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Jianfei
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NB40, Cleveland, OH 44195, USA. yiq@ccf.org.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase