Aurora, CO (Scicasts) - Viruses have evolved various mechanisms to evade host immunity and ensure efficient viral replication and persistence. 

Several DNA tumour viruses modulate host DNA methyltransferases for epigenetic dysregulation of immune-related gene expression in host cells. The host immune responses suppressed by virus-induced aberrant DNA methylation are also frequently involved in anti-tumour immune responses. 

"Ultimately, the virus is suppressing the immune system for its own benefit, and promoting the formation and proliferation of cancer cells may be just a side effect of that." says Dr. Sharon Kuss-Duerkop, research instructor working in the lab of CU Cancer Center investigator Dr. Dohun Pyeon.

Sharon Kuss-Duerkop and colleagues describe how viruses use methylation of DNA promoter regions to inactivate the immune system, causing cancer. Image: University of Colorado Cancer Center

Interestingly, while viruses certainly have the ability to edit human DNA - most obviously by inserting their own genetic code into DNA so that the new viruses are built alongside DNA replication - the review article explains that viruses do not necessarily turn off the immune system by editing genes. Instead, viruses mute the immune system by epigenetic regulation - instead of changing the actual code of genes, viruses change the degree to which genes are expressed.

They do this by a process called DNA methylation, which, very basically, is a way to silt over parts of the human genome to keep it from being read. In this case, viruses cause methylation of parts of the genome known as DNA promoter regions. Think of these promoter regions like on-off switches for next-door genes - when a promoter region is methylated, the switch is turned off and the gene it controls does not get read and expressed.

Model for DNA tumor virus-mediated DNA methylation to evade antiviral and antitumor immunity during viral persistence and carcinogenesis. (A) Cellular detection of viruses activates immune gene expression to induce an antiviral immune response. Proliferation of infected and neighboring cells can be blocked (black T bar) by immune-mediated apoptosis and/or cell cycle inhibition, which prevent cancer development. (B) DNA tumor viruses induce hypermethylation of immune genes that inhibit expression of antiviral immune genes (denoted by red “×”), resulting in immune evasion, which promotes (long red arrow) viral replication and persistence. Over long periods of time (multiple years), immune evasion and viral persistence can promote (short red arrow) cell proliferation and carcinogenesis. In addition, downregulation of immune gene expression by viral-induced DNA methylation may also contribute to host cell evasion of antitumor immune responses. Image: University of Colorado Cancer Center

"You get lack of access by things that would be driving transcription," Kuss-Duerkop says. In other words, by methylating DNA promoter regions, viruses can turn off genes. But the virus itself doesn't do this - it's not as if viruses creep along a length of DNA spitting out methyl groups onto DNA promoters. Instead, in a Machiavellian twist, viruses recruit human proteins to methylate DNA and thus turn off important other bits of human DNA.

"Viruses encode particular proteins that can in some way modulate DNA methyltransferases," Kuss-Duerkop says, meaning that viruses can cause our own proteins to over-methylate our own DNA.

Of course, it makes sense that viruses would choose to turn off genes that the immune system needs to fight the virus, "like interferon-b, which is a highly anti-viral gene expressed in virtually all cell types; or genes that T-cells need to recognize virus-infected cells," Kuss-Duerkop says.

The result is an immune system less able to fight the virus, and, if the virus causes cancer, a "microenvironment" near the tumour in which the immune system is suppressed. In fact, we see this in many cancers - tumours may specifically cloak themselves from the immune system, and they may also suppress the immune system more globally near the places they grow.

Sitting opposite these cancer-causing viruses and their ability to undercut the immune system are doctors and researchers who would like to recruit the immune system to attack cancer. Again, viruses turn down the immune system against the cancers they cause, and doctors would like to turn up the immune system against these same cancers.

And, in fact, these doctors and researchers are finding incredible success with this strategy; for example, PD-1 inhibitors remove this "cloak" that cancers use to hide from the immune system, and CAR-T cell therapies use specially engineered T-cells to seek cancer-specific proteins and destroy the cancer cells to which they are attached.

But challenges to immune-based therapies against cancer remain. Not least amongst which is the fact that while some patients respond to these therapies, others do not. The answer to increasing the effectiveness of immune therapies, or perhaps at least to choosing which patients are most likely to benefit from immune therapies, may lie in understanding the ways viruses (and cancers themselves) have evolved to evade the immune system.

Maybe if virus-related cancers have methylated DNA promoter regions of immune-related genes, the answer to increasing the effectiveness of immune-based therapies against cancer is to demethylate these genes.

"You don't want to just turn down methylation globally, which would result in over-activation of all genes in the cell, but demethylating some of these gene promoter regions selectively could revive an immune system muted by cancer-causing viruses," Kuss-Duerkop says.

"Ultimately viruses are causing these tumours to form and are further manipulating the immune system to allow tumours to keep growing," Kuss-Duerkop says. "But these same mechanisms may be key in combating tumours with immune-based therapies or in keeping cancer from developing in the first place."

Article adapted from a University of Colorado Anschutz Medical Campus news release. 

Publication: DNA Tumor Virus Regulation of Host DNA Methylation and Its Implications for Immune Evasion and Oncogenesis. Kuss-Duerkop, SK et al. Viruses (February 2018): Click here to view.