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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]
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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, Veterinary and Food Sciences |
| Research Group: | Veterinary sciences |
| Research Field: | Veterinary immunology |
| Objective Division: | Environmental Management |
| Objective Group: | Terrestrial systems and management |
| Objective Field: | Terrestrial biodiversity |
| UTAS Author: | Kreiss, A (Dr Alexandre Kreiss) |
| UTAS Author: | Tovar, C (Dr Cesar Tovar Lopez) |
| UTAS Author: | Hamede, R (Dr Rodrigo Hamede Ross) |
| UTAS Author: | Jones, ME (Professor Menna Jones) |
| UTAS Author: | Woods, GM (Professor Gregory Woods) |
| ID Code: | 84749 |
| Year Published: | 2013 |
| Web of Science® Times Cited: | 128 |
| Deposited By: | Menzies Institute for Medical Research |
| Deposited On: | 2013-05-30 |
| Last Modified: | 2017-11-01 |
| Downloads: | 361 View Download Statistics |
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