CDK6 als therapeutisches Target zur Prävention von NK-Zell-Alterung

Senescence is a natural process that restricts the growth of stressed or damaged cells and tends to increase as we age. The accumulation of senescent cells is linked to age-related tissue dysfunction and weakened immune responses, paving the way for various diseases. Among the immune players, Natural Killer (NK) cells play a pivotal role in combating tumors and microbial infections. However, as we age, the effectiveness of NK cells diminishes, and little is known about senescence within NK cells themselves. Recent advancements have allowed us to establish an in vitro NK cell senescence model, uncovering a key regulator of this process. Through experiments in aging mice, we have identified a subset of NK cells exhibiting signs of senescence. Cyclin-Dependent Kinase 6 (CDK6) plays a critical role in cell cycle regulation and has gained interest as a target in cancer therapy. However, inhibiting CDK4/6 can also affect the function of immune cells, influencing the immune system's ability to target cancer cells. Although evidence suggests that CDK6 is important in T cells, its role in NK cells remains unexplored. Using CDK6 knockout (KO) mouse models, a kinase-inactive version and CDK6 overexpressing mouse model, we observed that CDK6 is crucial in regulating NK cell senescence and their effector functions. Hypotheses/Objectives We hypothesize that CDK6 plays a pivotal role in driving NK cell senescence through kinase-dependent mechanisms. Our aim is to elucidate CDK6's contribution to NK cell aging and the induction and maintenance of senescence. We further aim to validate that targeting CDK6 or its downstream effectors in NK cells can prevent senescence and enhance anti-tumor capacity, making it an attractive target for immunotherapeutic approaches. Methods We will use NK cell in vitro senescence cultures and genetically modified mouse models for aging and in vivo tumor surveillance experiments to study NK cell senescence. To gain mechanistic insights we will perform RNA sequencing experiments, phosphoproteomics analysis and validations studies including CRISPR-Cas9 mediated KOs. The analysis of mouse data will be complemented with studies on human NK cells. Innovation We have little knowledge about the induction and consequences of NK cell senescence. The work will provide a deeper understanding of the role of CDK6 in NK cell function with a special emphasis on NK cell senescence. Our novel mouse models and the NK cell senescence models in vitro and in vivo will enable pioneering studies on the dynamics and mechanisms of NK cell senescence. The results might influence future NK cell based immunotherapeutic treatment strategies to bypass their functional decline.

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