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.