eCite Digital Repository

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

Citation

Siddle, HV and Kreiss, A and Tovar, C and Yuen, CK and Cheng, Y and Belov, K and Swift, K and Pearse, A-M and Hamede, R and Jones, ME and Skjodt, K and Woods, GM and Kaufman, J, Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer, Proceedings of the National Academy of Sciences of the United States of America, 110, (13) pp. 5103-5108. ISSN 0027-8424 (2013) [Refereed Article]


Preview
PDF
5Mb
  

Copyright Statement

Copyright 2013 The Authors-

DOI: doi:10.1073/pnas.1219920110

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 surfaceMHCmolecules 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. © PNAS 2013.

Item Details

Item Type:Refereed Article
Keywords:canine transmissible venereal tumor, immune evasion, transplantation, primary tumour
Research Division:Agricultural and Veterinary Sciences
Research Group:Veterinary Sciences
Research Field:Veterinary Immunology
Objective Division:Environment
Objective Group:Flora, Fauna and Biodiversity
Objective Field:Flora, Fauna and Biodiversity at Regional or Larger Scales
Author:Kreiss, A (Dr Alexandre Kreiss)
Author:Tovar, C (Dr Cesar Tovar Lopez)
Author:Hamede, R (Mr Rodrigo Hamede Ross)
Author:Jones, ME (Associate Professor Menna Jones)
Author:Woods, GM (Professor Gregory Woods)
ID Code:84749
Year Published:2013
Web of Science® Times Cited:60
Deposited By:Menzies Institute for Medical Research
Deposited On:2013-05-30
Last Modified:2017-11-01
Downloads:173 View Download Statistics

Repository Staff Only: item control page