title: Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer.
abstract: 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.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
authors.forename: Hannah V
authors.initials: HV
authors.lastname: Siddle
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kreiss
authors.forename: Cesar
authors.initials: C
authors.lastname: Tovar
authors.forename: Chun Kit
authors.initials: CK
authors.lastname: Yuen
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Katherine
authors.initials: K
authors.lastname: Belov
authors.forename: Kate
authors.initials: K
authors.lastname: Swift
authors.forename: Anne-Maree
authors.initials: AM
authors.lastname: Pearse
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Hamede
authors.forename: Menna E
authors.initials: ME
authors.lastname: Jones
authors.forename: Karsten
authors.initials: K
authors.lastname: Skjødt
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Woods
authors.forename: Jim
authors.initials: J
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D045744:Cell Line, Tumor; D056727:Endangered Species; D044127:Epigenesis, Genetic / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D008394:Marsupialia / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology / Q000662:veterinary*; D019139:Tumor Escape
chemical_list: D006649:Histocompatibility Antigens; D007371:Interferon-gamma