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

Sci Rep. 2016 Feb 23;6:21678. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Animals
  • Carcinoma, Merkel Cell / drug therapy
  • Carcinoma, Merkel Cell / genetics*
  • Carcinoma, Merkel Cell / immunology
  • Carcinoma, Merkel Cell / pathology
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Gene Silencing / drug effects
  • Gene Silencing / immunology*
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / immunology
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / immunology
  • Histones / genetics
  • Histones / immunology
  • Humans
  • Hydroxamic Acids / pharmacology
  • Killer Cells, Lymphokine-Activated / cytology
  • Killer Cells, Lymphokine-Activated / drug effects
  • Killer Cells, Lymphokine-Activated / immunology*
  • Mice
  • Mice, Inbred NOD
  • NK Cell Lectin-Like Receptor Subfamily K / genetics
  • NK Cell Lectin-Like Receptor Subfamily K / immunology
  • Plicamycin / analogs & derivatives
  • Plicamycin / pharmacology
  • Promoter Regions, Genetic / drug effects
  • Signal Transduction
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology
  • Vorinostat
  • Xenograft Model Antitumor Assays

Substances

  • Histocompatibility Antigens Class I
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • KLRK1 protein, human
  • MHC class I-related chain A
  • MICB antigen
  • NK Cell Lectin-Like Receptor Subfamily K
  • Vorinostat
  • mithramycin A
  • Histone Deacetylases
  • Plicamycin