title: Reversal of epigenetic silencing of MHC class I chain-related protein A and B improves immune recognition of Merkel cell carcinoma.
abstract: Merkel cell carcinoma (MCC) is a virally associated cancer characterized by its aggressive behavior and strong immunogenicity. Both viral infection and malignant transformation induce expression of MHC class I chain-related protein (MIC) A and B, which signal stress to cells of the immune system via Natural Killer group 2D (NKG2D) resulting in elimination of target cells. However, despite transformation and the continued presence of virally-encoded proteins, MICs are only expressed in a minority of MCC tumors in situ and are completely absent on MCC cell lines in vitro. This lack of MIC expression was due to epigenetic silencing via MIC promoter hypo-acetylation; indeed, MIC expression was re-induced by pharmacological inhibition of histone deacetylases (HDACs) both in vitro and in vivo. This re-induction of MICs rendered MCC cells more sensitive to immune-mediated lysis. Thus, epigenetic silencing of MICs is an important immune escape mechanism of MCCs.
authors.affiliation: Translational Skin Cancer Research, German Cancer Consortium (DKTK), University Hospital Essen, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Cathrin
authors.initials: C
authors.lastname: Ritter
authors.affiliation: Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: Kaiji
authors.initials: K
authors.lastname: Fan
authors.affiliation: Division of Dermatology and Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA.
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Paulson
authors.affiliation: Division of Dermatology and Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA.
authors.forename: Paul
authors.initials: P
authors.lastname: Nghiem
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Schrama
authors.affiliation: Translational Skin Cancer Research, German Cancer Consortium (DKTK), University Hospital Essen, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Becker
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D020868:Gene Silencing / Q000187:drug effects / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics* / Q000276:immunology; D006657:Histones / Q000235:genetics / Q000276:immunology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology; D008926:Plicamycin / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D000077337:Vorinostat; C066851:mithramycin A; D006655:Histone Deacetylases; D008926:Plicamycin