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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.

History

Publication title

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

Volume

110

Issue

13

Pagination

5103-5108

ISSN

0027-8424

Department/School

Menzies Institute for Medical Research

Publisher

Natl Acad Sciences

Place of publication

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

Rights statement

Copyright 2013 The Authors-

Repository Status

  • Open

Socio-economic Objectives

Terrestrial biodiversity

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