CDK8 a weapon to arm NK cells against leukemia

Although the existence of tumor surveillance remained controversial for much of the past century, there is now conclusive proof that the host immune system has an important role in the fight against cancer. Indeed, in 2013 the Science Magazine chose cancer immunotherapy as breakthrough of the year. Among the immune cells with the ability to eliminate tumor cells are natural killer (NK) cells. NK cells are part of the innate immune system and have a pivotal role in the eradication of virally infected and transformed cells. NK-cell development, proliferation and activity are tightly controlled by the absence or presence of distinct cytokines in bone marrow and spleen and at the site of inflammation. NK cells are currently attracting considerable attention for their part in the fight against minimal residual disease (MRD), dormant tumor cells that are highly resistant to conventional chemotherapy and that may survive for years in patients even after full clinical remission. MRD poses a particular problem for the treatment of leukemia, as leukemic stem cells (LSCs) may reside for years in the bone marrow. Recent evidence suggests a correlation between relapse and NK cell activity in patients. We plan to use murine models of leukemia to test whether NK cells can eradicate LSCs and thus combat MRD. In addition we have recently shown that CDK8-mediated STAT1-S727 phosphorylation inhibits NK cell activation and antagonizes anti-tumor functions. We now plan to test whether inhibition of CDK8 represents a potential strategy to block STAT1-S727 phosphorylation and to enhance NK cell cytotoxicity, thereby improving tumor surveillance. The proposed project will address two key issues: (i) whether and which LSCs represent targets of NK cell cytotoxicity in MRD and (ii) the role of CDK8 in NK cells and NK cell-mediated immune surveillance.

CDK8 belongs to the family of cyclin-dependent kinases, which are currently in the focus of cancer research. Intense attempts to block this kinase family are ongoing. We have shown in the past that CDK8 is a key molecule in Natural killer cells (NK-cells), which are part of the immune system surveying tumor cells. In this study we focused on a leukemia model that is under the immune control of NK-cells. We found that CDK8 is also of great importance in the leukemic cells themselves. In the absence of CDK8, the cells undergo cell death significantly more readily. This effect was not recapitulated by blocking only the kinase function of CDK8. In summary CDK8 blocks leukemia formation in a dual manner - by interfering with NK cells and by blocking leukemic cell survival. To achieve that it is necessary to inhibit the entire protein - not only the kinase function. We have extended our knowledge to breast cancer. In triple negative breast cancer - a highly aggressive type of cancer - CDK8 is essential as it drives metastasis and blocks the ability of NK cells to recognize and eliminate these cells. In breast cancer, CDK8 functions as a break and masks tumor cells from the immune recognition. Also in this cancer the effects of CDK8 are kinase-independent and it is essential to block the entire molecule not only the kinase function.