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Epigenetic Regulation Allows Devil Facial Tumor Disease to Evade Immune System

NEW YORK (GenomeWeb News) – Epigenetic regulation of genes involved in antigen processing for display by the major histocompatibility complex allows devil facial tumor disease cells to evade the immune system of its host, the Tasmanian devil, researchers from the University of Cambridge, the University of Tasmania, and elsewhere reported today in the Proceedings of the National Academy of Sciences.

Devil facial tumor disease is a contagious cancer infecting Tasmanian devils that may be driving them to extinction. The devil immune system, though, appears to reject few, if any, of the invading DFTD cells.

Typically, the host adaptive immune system surveys and recognizes intruders like DFTD cells based on how host T cells interact with antigens presented by MHC class I and MHC class II molecules on the cell surfaces of the invading cells. In this study, though, the researchers reported that DFTD cells do not express MHC molecules on their cell surfaces. Regulatory changes, including epigenetic changes, appear to down-regulate genes involved in the antigen processing pathway.

"DFTD cells do not express functional MHC class I molecules in vitro and in vivo, explaining how DFTD escapes the T-cell response typical of allograft rejection," Hannah Siddle, a Cambridge postdoctoral researcher and the first author of the PNAS study, and her colleagues wrote.

However, the researchers also showed that a recombinant cytokine can be used to restore MHC class I molecules to the surfaces of DFTD cells. This suggests to the researchers that modified DFTD cells could be used to develop a vaccine for the disease.

"Developing a vaccine based on our research could tip the balance in the favor of the devil and give them a fighting chance," Siddle said in a statement.

In this study, the researchers first developed antibodies against the Tasmanian devil MHC class I heavy chain and the β2m domain, which helps stabilize the heavy chain, to determine whether MHC was actually expressed in four DFTD cell lines and one devil fibroblast cell line. By western blot, they found that only a fraction of MHC class I protein was expressed in the DFTD cells as compared to devil fibroblasts, and no β2m was. They further found through immunohistochemistry that DFTD had much lower levels of the β2m present than the fibroblast cells did. But by RT-PCR and RT-qPCR, the researchers noted that DFTD cells expressed class I heavy chains and class II B RNA transcripts.

In addition, other genes, such as TAP1, TAP2, and β2m genes, that are needed for MHC antigen processing are only very lowly expressed or not expressed at all in those cell lines, the researchers reported. A similar pattern held true for three tumor biopsies as compared to matched host spleen samples.

Additionally, the researchers found no evidence of structural changes affecting the DFTD transcripts or promoters for β2m, TAP1, TAP2, or MHC class I genes.

However, "[t]he combined loss of β2m and TAP in tumor cells suggested a common regulatory mechanism suppressing the transcription of these genes," Siddle and her colleagues wrote.

While bisufite sequencing of CpG islands near β2m and TAP1 promoters show no methylation differences between DFTD cells and fibroblasts, the researchers found that treating DFTD cells with a histone deacetylase inhibitor led to higher expression levels of β2m, TAP1, TAP2, and MHC class I transcripts. And, after treatment, class I MHC protein could be detected in DFTD cells via western blot, though the amount of β2m on DFTD cell surfaces increased by very little, if at all. But by expressing a recombinant devil cytokine, IFN-γ, in DFTD cells, the researchers were able to force the restoration β2m to DFTD cell surfaces.

"[The] loss of MHC molecules from the cell surface of DFTD cells is due to coordinated down-regulation of genes essential to the antigen-processing pathway, and … this loss is by regulatory mechanisms including epigenetic modifications rather than structural mutations," the researchers concluded.

The restoration of MHC molecules to the cell surface of DFTD cells indicates that such cells could be used as a vaccine against devil facial tumor disease, the researchers said. "A whole-cell vaccine would expose devil T cells to antigenic peptides derived from the DFTD cells and presented by foreign MHC molecules," Siddle and her colleagues wrote. "Upon subsequent challenge with wild-type DFTD cells, host cells should be activated against those antigens found even at low levels on the surface of DFTD cells and/or intracellular antigens released by DFTD cells during tumor growth."

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