Type I and II interferons inhibit Merkel cell carcinoma via modulation of the Merkel cell polyomavirus T-antigens

203 words) Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer associated with the Merkel cell polyomavirus (MCV). As MCC cell lines demonstrate oncogene addiction to the MCV T-antigens, pharmacological 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 interferons (IFNs) on MCC cell lines, especially on MCV positive (MCV+) lines. Type I IFNs (i.e. Multiferon, a mix of different IFN subtypes, and IFN ) strongly inhibited the cellular viability. Cell cycle analysis demonstrated increased sub-G fractions for these cells upon IFN treatment indicating apoptotic cell death; these effects were less pronounced for IFN . 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 protein (PML), which is known to interfere with the function of the LTA. In addition, the intra-tumoural application of multiferon resulted in a regression of MCV+ but not MCVMCCs in vivo. Together, our findings demonstrate that type I IFNs have a strong anti-tumour effect, which is at least in part explained by modulation of the virally encoded LTA. Research. on October 23, 2017. © 2012 American Association for Cancer cancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 2, 2012; DOI: 10.1158/0008-5472.CAN-11-2651