Inhibition of glucose uptake increase serial-killing capacity of NK cells

Abstract Background Tumor cells rely heavily on glycolysis to meet their high metabolic demands. While this results in nutrient deprivation within the tumor microenvironment and has negative effects on infiltrating immune cells such as NK cells, it also creates a potential target for cancer therapies. Methods Here we use Glupin, an inhibitor of glucose transporters, to study the effect of limited glucose uptake on Natural Killer cells and their anti-tumor functions. Results Glupin treatment effectively inhibited glucose uptake and restricted glycolysis in NK cells. However, acute treatment had no negative effect on NK cell cytotoxicity or cytokine production. Long-term restriction of glucose uptake by Glupin treatment only delayed NK cell proliferation as they could switch to glutaminolysis as alternative energy source. While IFN-g production was partially impaired, long-term Glupin treatment had no negative effect on degranulation. Interestingly, the serial killing activity of NK cells was even enhanced, possibly due to changes in NAD metabolism. Conclusion This demonstrates that NK cell cytotoxicity is remarkably robust and insensitive to metabolic disturbances and makes cellular metabolism an attractive target for immune-mediated tumor therapies.