A new study shows how the immune system reacts to cancer

Three University of Colorado Cancer Center researchers as part of a team that recently published a paper offer a new perspective on how the immune system relates to cancer. Quentin Vicens, PhD, Jeffrey Kieft, PhD, and Beat Vögeli, PhD, are the authors of the paper, which looks at how an enzyme called ADAR1 works in cancer-related pathways.

“In a cell, ADAR1 modulates native RNA – or self-RNA – so that the cell recognizes it as its own. It is a key defense against autoimmune disorders,” Kieft says. “But if there is a virus, viral RNA is not secreted by ADAR1, so that cell can recognize and respond. The cell knows it has foreign RNA, and it activates immune responses to fight the against that disease. “

For their paper published last month in the magazine Nature Communication, Kieft, Vögeli, Vicens, and the rest of the team — including Parker Nichols, a graduate student in the Structural Biology and Biochemistry program at the CU School of Medicine who work together in work — Kieft and Vögeli blade – looking at where that is in particular the ADAR1 binds to RNA to complete the editing process. They already knew of a domain of ADAR1 called Z-alpha binding to a type of RNA called Z-RNA, but they found that Z-alpha ADAR1 can bind to other forms of RNA as well.

The team asked, ‘How does Z-alpha identify all those places in RNA if they don’t appear to be doing Z-RNA? One of the take home messages is that other forms of RNA can bind to Z-alpha ADAR1 and even form part of Z-RNA. That was surprising because it shows that RNA can create this unique Z structure in previously unknown places. “

Jeffrey Kieft, PhD, Study Author, CU School of Medicine

The team is now proposing a model for how Z-alpha ADAR1 can bind to different types of RNA. It is an important finding in cancer research because of the role of ADAR1 in cancer management. A normally functioning immune system can detect cancerous cells and then destroy them, but if too much ADAR1 editing takes place, a cell could suppress the immune response in an attempt to protect herself.

“In many cancers, there is an increase in ADAR1; it does more than it should,” Kieft says. “Too much ADAR1 seems to lead to more RNA editing than normal. This is going to mismanage things, affecting specific regions of RNA or RNA types.

The extra edit is going to throw off the normal immune response, but it seems to have a lot of other side effects in the cell as well. Cancer is a disease where gene regulation has gone awry, so if an important regulatory pathway such as ADAR preparation has become severe, that can contribute to cancer. “

Knowing all the targets of ADAR1 in a cell is also a step towards more effective treatments, Kieft says. If researchers understand the pathways, they may be able to find a way to stop the overactive preparation process and increase an immune response. It is a finding that is relevant to many other diseases as well – Vögeli says since the paper was published, the researchers have heard from other scientists across the country who are interested in ADAR1.

“We’ve received a lot of feedback on the paper,” he says. “There’s a lot of interest in this area right now, and other people are interested in how they could improve our structured information. used. “

Vögeli and Vicens are now organizing a meeting with a focus on the ADAR1 function and compiling specific issues of the journals Molecules and International Journal of Molecular Sciences.

Vicens says the research project also highlights the importance of collaborative working and openness to new directions. “I brought a new project and direction to the Kieft lab when I joined,” Vicens says. “Both labs were open to support it strategically and financially, and the resulting effort allowed a team to investigate what would otherwise not have been possible. “