title: Type I and II IFNs inhibit Merkel cell carcinoma via modulation of the Merkel cell polyomavirus T antigens.
abstract: Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer associated with the Merkel cell polyomavirus (MCV). As MCC cell lines show oncogene addiction to the MCV T antigens, pharmacologic interference of the large T antigen (LTA) may represent an effective therapeutic approach for this deadly cancer. In this study, we investigated the effects of IFNs on MCC cell lines, especially on MCV-positive (MCV(+)) lines. Type I IFNs (i.e., Multiferon, a mix of different IFN-α subtypes, and IFN-β) strongly inhibited the cellular viability. Cell-cycle analysis showed increased sub-G fractions for these cells upon IFN treatment indicating apoptotic cell death; these effects were less pronounced for IFN-γ. Notably, this inhibitory effect of type I IFNs on MCV(+) MCC cell lines was associated with a reduced expression of the MCV LTA as well as an increased expression of promyelocytic leukemia (PML) protein, which is known to interfere with the function of the LTA. In addition, the intratumoral application of Multiferon resulted in a regression of MCV(+) but not MCV(-) MCCs in vivo. Together, our findings show that type I IFNs have a strong antitumor effect, which is at least in part explained by modulation of the virally encoded LTA.
authors.affiliation: Department of Dermatology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Willmes
authors.forename: Christian
authors.initials: C
authors.lastname: Adam
authors.forename: Miriam
authors.initials: M
authors.lastname: Alb
authors.forename: Lena
authors.initials: L
authors.lastname: Völkert
authors.forename: Roland
authors.initials: R
authors.lastname: Houben
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Becker
authors.forename: David
authors.initials: D
authors.lastname: Schrama
mesh_terms: D000818:Animals; D000957:Antigens, Viral, Tumor / Q000276:immunology*; D015266:Carcinoma, Merkel Cell / Q000276:immunology* / Q000821:virology; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D059965:Merkel cell polyomavirus / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D027601:Polyomavirus Infections / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology* / Q000821:virology
chemical_list: D000957:Antigens, Viral, Tumor; D007370:Interferon Type I; D007371:Interferon-gamma