title: T-cell responses to oncogenic merkel cell polyomavirus proteins distinguish patients with merkel cell carcinoma from healthy donors.
abstract: OBJECTIVE
  Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with strong evidence of viral carcinogenesis. The association of MCC with the Merkel cell polyomavirus (MCPyV) may explain the explicit immunogenicity of MCC. Indeed, MCPyV-encoded proteins are likely targets for cytotoxic immune responses to MCC as they are both foreign to the host and necessary to maintain the oncogenic phenotype. However, to date only a single MCPyV-derived CD8 T-cell epitope has been described, thus impeding specific monitoring of T-cell responses to MCC.
  
  
  METHODS
  To overcome this limitation, we scanned the MCPyV oncoprotein large T and small T antigens and the virus capsid protein VP1 for potential T-cell epitopes, and tested for MHC class I affinity. We confirmed the relevance of these epitopes using a high-throughput platform for T-cell enrichment and combinatorial encoding of MHC class I multimers.
  
  
  RESULTS
  In peripheral blood from 38 patients with MCC and 30 healthy donors, we identified 53 MCPyV-directed CD8 T-cell responses against 35 different peptide sequences. Strikingly, T-cell responses against oncoproteins were exclusively present in patients with MCC, but not in healthy donors. We further demonstrate both the processing and presentation of the oncoprotein-derived epitopes, as well as the lytic activity of oncoprotein-specific T cells toward MHC-matched MCC cells. Demonstrating the presence of oncoprotein-specific T cells among tumor-infiltrating lymphocytes further substantiated the relevance of the identified epitopes.
  
  
  CONCLUSIONS
  These T-cell epitopes represent ideal targets for antigen-specific immune therapy of MCC, and enable tracking and characterization of MCPyV-specific immune responses.
authors: Authors' Affiliations: Center for Cancer Immune Therapy (CCIT), Department of Hematology, University Hospital Herlev, Herlev, Denmark; General Dermatology, Medical University of Graz, Graz, Austria; Departments of Medicine/Dermatology, Pathology, University of Washington; Fred Hutchinson Cancer Research Center, Seattle Cancer Center Care Alliance, Seattle, Washington; and Department of Oncology, University Hospital Herlev, Herlev, Denmark.
authors: Rikke
authors: R
authors: Lyngaa
authors: Natasja Wulff
authors: NW
authors: Pedersen
authors: David
authors: D
authors: Schrama
authors: Charlotte Albæk
authors: CA
authors: Thrue
authors: Dafina
authors: D
authors: Ibrani
authors: Ozcan
authors: O
authors: Met
authors: Per
authors: P
authors: Thor Straten
authors: Paul
authors: P
authors: Nghiem
authors: Jürgen C
authors: JC
authors: Becker
authors: Sine Reker
authors: SR
authors: Hadrup
mesh_terms: D063646:Carcinogenesis / Q000276:immunology; D015266:Carcinoma, Merkel Cell / Q000175:diagnosis / Q000235:genetics* / Q000821:virology; D000939:Epitopes / Q000276:immunology / Q000302:isolation & purification; D006801:Humans; D007113:Immunity, Innate; D059965:Merkel cell polyomavirus / Q000235:genetics / Q000472:pathogenicity*; D012878:Skin Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology; D014764:Viral Proteins / Q000302:isolation & purification
chemical_list: D000939:Epitopes; D014764:Viral Proteins