Tumor and Stem Cell Biology Type I and II IFNs Inhibit Merkel Cell Carcinoma via Modulation of the Merkel Cell Polyomavirus T Antigens

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 onMCC cell lines, especially onMCV-positive (MCVþ) lines. Type I IFNs (i.e., Multiferon, a mix of different IFN-a subtypes, and IFN-b) strongly inhibited the cellular viability. Cellcycle analysis showed increased sub-G fractions for these cells upon IFN treatment indicating apoptotic cell death; these effects were less pronounced for IFN-g . Notably, this inhibitory effect of type I IFNs on MCVþ 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 MCVþ but not MCV MCCs in vivo. Together, ourfindings show that type I IFNs have a strong antitumor effect, which is at least in part explained bymodulation of the virally encoded LTA. Cancer Res; 72(8); 2120–8. 2012 AACR.