Unraveling of the role and the regulation of hypoxia-inducible factors in natural killer cell functioning in hypoxic and stimulating environments.

Natural killer (NK) cells are potent cytotoxic cells from the hematopoietic system, playing an important role in the control of infection and malignancy. NK cells often operate under harsh conditions, such as in deprived oxygen or hypoxia. Hypoxia stabilizes its primary regulators hypoxia-inducible factors (HIF), more specifically HIF-1? and HIF-2?. While hypoxia reduces NK cell-mediated cytotoxicity, data on other NK cell features is conflicting. In addition, the role of HIF in NK cells has been neglected, as only one mouse study demonstrated that HIF-1? ablation in NK cells indirectly reduces tumor load via angiogenic rather than cytotoxic effects. However, murine NK cells show quite some disparities to human NK cells. In addition to hypoxia, also stimuli such as cytokines can stabilize HIF. Hence, HIF could play a pivotal role in NK cells. Therefore, this project aims to gain fundamental insights in the role and regulation of HIF in human NK cells via combining omics with functional assays. First, we will unravel the effect of hypoxia on (stimulated) NK cells. Next, we will dissect the divergent roles of HIF-1? and HIF-2? in the functioning of NK cells in response to hypoxic and stimulatory conditions. HIF isoform-specific knockout NK cells will be created using CRISPR-Cas9. Finally, we will elucidate how HIF isoforms regulate their effects in NK cells. The obtained knowledge could prove extremely valuable in rational guidance of rising novel NK-cell based immunotherapies.

Keywords:NATURAL KILLER CELLS, HYPOXIA

Disciplines:Hematology, Innate immunity, Cancer therapy, Cell physiology, Cell therapy