Reversal of epigenetic silencing of MHC class I chain-related protein A and B improves immune recognition of Merkel cell carcinoma.

Cathrin Ritter,Paul Nghiem,Kaiji Fan,Kelly G Paulson,David Schrama,Jürgen C Becker

doi:10.1038/srep21678

Abstract

Merkel cell carcinoma (MCC) is a virally associated cancer characterized by its aggressive behavior and strong immunogenicity. Both viral infection and malignant transformation induce expression of MHC class I chain-related protein (MIC) A and B, which signal stress to cells of the immune system via Natural Killer group 2D (NKG2D) resulting in elimination of target cells. However, despite transformation and the continued presence of virally-encoded proteins, MICs are only expressed in a minority of MCC tumors in situ and are completely absent on MCC cell lines in vitro. This lack of MIC expression was due to epigenetic silencing via MIC promoter hypo-acetylation; indeed, MIC expression was re-induced by pharmacological inhibition of histone deacetylases (HDACs) both in vitro and in vivo. This re-induction of MICs rendered MCC cells more sensitive to immune-mediated lysis. Thus, epigenetic silencing of MICs is an important immune escape mechanism of MCCs.

Highlights

Natural Killer group 2D (NKG2D) is a lectin-like type 2 transmembrane receptor encoded by the gene Klrk[1] and is part of a critical pathway signaling cellular stresses to the innate and adaptive immune system
Merkel cell carcinoma (MCC) tumors express low levels of MICA and MICB mRNAs. Since both viral infection and malignant transformation induce expression of the immune activating NKG2D ligands MICA and MICB, we screened for the respective mRNA expression among 75 MCC tumors from 61 patients and a number of MCC cell lines
In Merkel cell polyomavirus (MCPyV) positive tumors, MICB mRNA expression correlated with the gene expression signature for infiltrating immune competent cells, a feature that had been associated with a good prognosis previously[15] (Supplementary Fig. 2)

Summary

Introduction

Natural Killer group 2D (NKG2D) is a lectin-like type 2 transmembrane receptor encoded by the gene Klrk[1] (killer cell lectin-like receptor subfamily member 1) and is part of a critical pathway signaling cellular stresses to the innate and adaptive immune system. The importance of MICA and MICB induced NKG2D-signaling for immune surveillance of virally infected and transformed cells is highlighted by the fact that viruses and cancer cells have developed mechanisms to interfere with this interaction[14]. These mechanisms include shedding of surface expressed molecules, binding and retaining of MICA and MICB proteins in the cytoplasm, over-expression of MICA and MICB mRNA-targeting microRNAs, as well as other epigenetic mechanisms such as chromatin remodeling[14,20]. These findings open new avenues for therapy of advanced MCC in combination with immune modulating molecules such as immune checkpoint blocking antibodies

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Results

Conclusion