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

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posted on 2023-05-17, 17:58 authored by Siddle, HV, Kreiss, A, Cesar Tovar LopezCesar Tovar Lopez, Yuen, CK, Cheng, Y, Belov, K, Swift, K, Pearse, A-M, Rodrigo Hamede RossRodrigo Hamede Ross, Menna JonesMenna Jones, Skjodt, K, Gregory WoodsGregory Woods, Kaufman, J
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.


Publication title

Proceedings of the National Academy of Sciences of the United States of America










Menzies Institute for Medical Research


Natl Acad Sciences

Place of publication

2101 Constitution Ave Nw, Washington, USA, Dc, 20418

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Copyright 2013 The Authors-

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  • Open

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