Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer

• DOI: 10.1073/pnas.1219920110
• Publication Date: 2013-03-12T01:09:22Z
• Authors: Hannah V. Siddle; Alexandre Kreiss; Cesar Tovar; Chun Kit Yuen; Yuanyuan Cheng; Katherine Belov; Kate Swift; Anne-Maree Pearse; Rodrigo Hamede; Menna E. Jones; Karsten Skjødt; Gregory M. Woods; Jim Kaufman
• Keywords: 0301 basic medicine; 570; Skin Neoplasms; Primary tumour; 610; Canine transmissible venereal tumor; Cell Line; Epigenesis, Genetic; Interferon-gamma; 03 medical and health sciences; Genetic; Cell Line, Tumor; Histocompatibility Antigens; Animals; Transplantation; Neoplastic; Antigen Presentation; Tumor; Immune evasion; Endangered Species; 3. Good health; Gene Expression Regulation, Neoplastic; Marsupialia; Gene Expression Regulation; Tumor Escape; Epigenesis

Contagious cancers that pass between individuals as an infectious cell line are highly unusual pathogens. Devil facial tumor disease (DFTD) is one such contagious cancer that emerged 16 y ago and is driving the Tasmanian devil to extinction. As both a pathogen and an allograft, DFTD cells should be rejected by the host–immune response, yet DFTD causes 100% mortality among infected devils with no apparent rejection of tumor cells. Why DFTD cells are not rejected has been a question of considerable confusion. Here, we show that DFTD cells do not express cell surface MHC molecules in vitro or in vivo, due to down-regulation of genes essential to the antigen-processing pathway, such as β2-microglobulin and transporters associated with antigen processing. Loss of gene expression is not due to structural mutations, but to regulatory changes including epigenetic deacetylation of histones. Consequently, MHC class I molecules can be restored to the surface of DFTD cells in vitro by using recombinant devil IFN-γ, which is associated with up-regulation of the MHC class II transactivator, a key transcription factor with deacetylase activity. Further, expression of MHC class I molecules by DFTD cells can occur in vivo during lymphocyte infiltration. These results explain why T cells do not target DFTD cells. We propose that MHC-positive or epigenetically modified DFTD cells may provide a vaccine to DFTD. In addition, we suggest that down-regulation of MHC molecules using regulatory mechanisms allows evolvability of transmissible cancers and could affect the evolutionary trajectory of DFTD.