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 þ ) 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 MCV þ 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 þ but not MCV À 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. Cancer Res; 72(8); 2120-8. Ó2012 AACR.

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

“…Importantly, treatment of MCC cell lines with type-I interferons, etoposide (a standard MCC chemotherapeutic) and radiation, can all induce MHC-I upregulation in vitro [52]. Notably, in vitro treatment of MCC cells lines with type-I interferons also reduced expression of MCPyV LT, which may further promote tumor destruction [53]. Downregulation of MHC-I can also be reversed in vivo and will be discussed subsequently in the context of intralesional IFN treatment.…”

Immunotherapy with Imiquimod and Interferon Alfa for Metastasized Merkel Cell Carcinoma

“…Epidemiologic and experimental evidence both strongly suggest that mcc is controlled by the immune system [18][19][20][21][22] . Advanced age and immunosuppression favour the development of mcc and are suggested to be responsible for a strong rise in the incidence of mcc since the mid-1980s 18 .…”

Interaction between Merkel cell carcinoma and the immune system: Pathogenetic and therapeutic implications

“…In particular, type I IFN is able to induce apoptosis in MCPyV + MCC cell lines in vitro and in vivo through the modulation of the virally encoded LTA: IFN type I reduces the expression of the MCV LT and increases the expression of promyelocytic leukemia (PML) protein, which interferes with the function of the LT (30). Furthermore, a multicenter study revealed that isolated hyperthermic limb perfusion with tumor necrosis factor-α, IFN-γ, and melphalan resulted in a complete or partial response of locally advanced MCC (31).…”