Short-term Hypoxia Exposure Enhances Tumor-killing Activity of Natural Killer Cells

초록

Although natural killer (NK) cells are promising agents for cell-based cancer therapy, NK cells show limited performance in destroying tumors than T cells. To overcome this limitation, efforts are ongoing to enhance the anti-tumor activity of NK cells. In the present study, NK cells are exposed to hypoxic conditions for a short period using sodium sulfite and cobalt chloride. Hypoxia-inducible factor-1α (HIF-1α) is stabilized in chemically induced hypoxic conditions by showing that HIF-1α expression level increased in short-term hypoxia exposed NK (sHyp-NK) cells. The expression of cytolytic activity-related genes, such as NKG2D, NKp44, granzyme B, and perforin, increased in sHyp-NK cells. However, the expression of the inhibitory receptor, NKG2A, did not change. In addition, NKG2D expression is upregulated on both the membrane surface and intracellular pool. These effects are suppressed when HIF-1α is inhibited during early short-term hypoxia exposure. Moreover, the anti-tumor activity of sHyp-NK cells is significantly enhanced when they encounter target cells both in normoxia and hypoxia. Collectively, these results demonstrate that early short-term hypoxic exposure can enhance the anti-tumor activity of NK cells by upregulating the activating receptors and cytolytic activity-related genes of NK cells, which are probably associated with HIF-1α stabilization.