31 MCPyV and the immune system: Target and modulator

Abstract

Merkel cell carcinoma (MCC) is a aggressive skin cancer associated with the Merkel cell polyomavirus (MCPyV). Presence of tumor-infiltrating lymphocytes and immune competence are strongly correlated with the course of the disease. MCPyV encoded proteins should be highly effective targets for cytotoxic immune responses as they are both foreign to the host and specific for the infection. Srutinizing for T-cell responses against MCPyV proteins revealed responses against HLA-A1, -A2, -A3, -A11 and -B7 restricted epitopes derived from both Large and Small T antigen in MCC patients. Moreover, we demonstrate the processing and presentation of the oncoprotein derived peptides, as well as the functional activity of the T antigen-reactive T cells. Despite the expression of immunogenic viral proteins and the presence of reactive cytotoxic T cell, MCCs are able to evade the immune system. Infected transformed cells in general express activating NKG2D ligands such as MICA/B activating cellular immune responses. However, in none of the MCPyV positive MCC cell lines MICA/B were expressed on transcriptional or translational level. Immunohistochemistry of 54 MCC tumors further revealed that in the majority MICA was not detectable. Since MICA/B expression is frequently silenced by histone deacetylation the effect of the HDAC inhibitor SAHA was tested revealing an induction of MICA/B resulting in an boosted lysis by cytotoxic lymphocytes. Accordingly, ChIP analysis demonstrated enhanced Histone H3 acetylation of the MICA/B promoters. Thus, MCPyV derived epitopes elicit cytotoxic T-cell responses which can be rendered functional effective by induction of NKG2D Ligand expression.