title: Downregulation of MHC-I expression is prevalent but reversible in Merkel cell carcinoma.
abstract: Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-associated skin cancer. Robust cellular immune responses are associated with excellent outcomes in patients with MCC, but these responses are typically absent. We determined the prevalence and reversibility of major histocompatibility complex class I (MHC-I) downregulation in MCC, a potentially reversible immune-evasion mechanism. Cell-surface MHC-I expression was assessed on five MCC cell lines using flow cytometry as well as immunohistochemistry on tissue microarrays representing 114 patients. Three additional patients were included who had received intralesional IFN treatment and had evaluable specimens before and after treatment. mRNA expression analysis of antigen presentation pathway genes from 35 MCC tumors was used to examine the mechanisms of downregulation. Of note, 84% of MCCs (total n = 114) showed reduced MHC-I expression as compared with surrounding tissues, and 51% had poor or undetectable MHC-I expression. Expression of MHC-I was lower in polyomavirus-positive MCCs than in polyomavirus-negative MCCs (P < 0.01). The MHC-I downregulation mechanism was multifactorial and did not depend solely on HLA gene expression. Treatment of MCC cell lines with ionizing radiation, etoposide, or IFN resulted in MHC-I upregulation, with IFNs strongly upregulating MHC-I expression in vitro, and in 3 of 3 patients treated with intralesional IFNs. MCC tumors may be amenable to immunotherapy, but downregulation of MHC-I is frequently present in these tumors, particularly those that are positive for polyomavirus. This downregulation is reversible with any of several clinically available treatments that may thus promote the effectiveness of immune-stimulating therapies for MCC.
authors.affiliation: Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington.
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Paulson
authors.affiliation: Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tegeder
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Willmes
authors.affiliation: Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington.
authors.forename: Jayasri G
authors.initials: JG
authors.lastname: Iyer
authors.affiliation: Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington.
authors.forename: Olga K
authors.initials: OK
authors.lastname: Afanasiev
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Würzburg, Germany. Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Schrama
authors.affiliation: Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Koba
authors.affiliation: Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington.
authors.forename: Renee
authors.initials: R
authors.lastname: Thibodeau
authors.affiliation: Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Nagase
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington. Department of Laboratory Medicine, University of Washington, Seattle, Washington.
authors.forename: William T
authors.initials: WT
authors.lastname: Simonson
authors.affiliation: Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington.
authors.forename: Aaron
authors.initials: A
authors.lastname: Seo
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington. Department of Medicine, Division of Infectious Disease, University of Washington, Seattle, Washington. Department of Global Health, University of Washington, Seattle, Washington. Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: David M
authors.initials: DM
authors.lastname: Koelle
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Margaret
authors.initials: M
authors.lastname: Madeleine
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, Washington.
authors.forename: Shailender
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: Department of Dermatology, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Department of Dermatology, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Sano
authors.affiliation: Merck and Co. Inc., West Point, Pennsylvania.
authors.forename: James S
authors.initials: JS
authors.lastname: Hardwick
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, Washington.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
authors.affiliation: Merck and Co. Inc., West Point, Pennsylvania.
authors.forename: Michele A
authors.initials: MA
authors.lastname: Cleary
authors.affiliation: Department of Dermatology, Medical University of Graz, Graz, Austria. Department for Translational Dermato-Oncology (DKTK), University Hospital Essen, Essen, Germany.
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Becker
authors.affiliation: Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington. Department of Pathology, University of Washington, Seattle, Washington. Fred Hutchinson Cancer Research Center, Seattle, Washington. pnghiem@uw.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Nghiem
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy / Q000276:immunology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D016899:Interferon-beta / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology*; D046888:Tissue Array Analysis; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D016899:Interferon-beta