11.04.2018: The human immune system uses natural killer (NK) cells as a weapon against cancer and virus-infected cells. A higher activity of the NK cells corresponds directly to a higher effectiveness in fighting tumors. Researchers at Vetmeduni Vienna have now shown in a study published in Cancer Immunology Research that it is possible to enhance NK cell activity even further by deleting the CDK8 gene. Until now, CDK8 is known to have an important role in the formation of tumors, where its activity is often amplified. Inhibiting CDK8 activity is the object of several current studies.

Decades have been spent investigating how cancer cells manage to reproduce while evading the control of the immune system. So-called immunotherapies are currently being researched as a way to strengthen the body’s immune system response against tumors. Researchers from the Institute of Pharmacology and Toxicology at Vetmeduni Vienna, with first author Agnieszka Witalisz-Siepracka, have made important progress in this direction. They show how the activity of NK cells against tumors can be enhanced through the deletion of the CDK8 gene. CDK8 is a cyclin-dependent kinase that controls several vital functions within human cells. When CDK8 is hyperactive, it can result in cell transformation.

In their study in Cancer Immunology Research, the researchers focused on the tumor surveillance system. They were able to show that CDK8 plays a special part in NK cells, where it suppresses their activity. By deleting CDK8, the research team succeeded in significantly restricting tumor growth in mice. Witalisz-Siepracka draws the following conclusions: “Deletion of CDK8 led to increased activation of the NK cells. You could say they became ‘armed’. Their ability to kill grew and the tumor shrank.”

This study builds on a previously published study by the same research group in which the researchers had postulated that CDK8 has a pivotal role in the killing activity of NK cells in cell culture models. Now they have gone an important step further by transferring their knowledge to tumor growth in vivo. “This had not been confirmed in a living organism before,” says Witalisz-Siepracka. “Because there are currently a number of preclinical studies on the development of CDK8 inhibitors, we wanted to determine the effects CDK8 deletion would have on the NK cells.”

“Arming” an immunological weapon through the deletion of CDK8

The researchers obtained their research results by using specially designed mice with selective deletion of CDK8 in NK cells. “We need a new class of CDK8 inhibitors for immunotherapy. Such an inhibitor would have to trigger the breakdown of the entire CDK8 protein. In addition to the tumor cell-intrinsic effect, the immune system would also be activated to fight the tumor cells. The result would be a double blow against the cancer cells.” Senior author Veronika Sexl summarizes the findings: “Degradation of CDK8 could be a promising way to fight tumors using the body’s own arsenal.”

The article “NK Cell-Specific CDK8 Deletion Enhances Antitumor Responses” by Agnieszka Witalisz-Siepracka, Dagmar Gotthardt, Michaela Prchal-Murphy, Zrinka Didara, Ingeborg Menzl, Daniela Prinz, Leo Edlinger, Eva Maria Putz and Veronika Sexl was published in Cancer Immunology Research.