Natural Killer (NK) cells provide important protection from cancer and are a key requirement for particular immunotherapies. In activated NK cells, a metabolic response towards increased glycolysis and oxidative phosphorylation is crucial for NK cell effector functions. However, there is accumulating evidence that NK cells become dysfunctional during chronic inflammatory diseases, such as human breast cancer. This dysfunction is apparent in peripheral blood NK cells and can impact on normal NK cell immune responses and their effective targeting during immunotherapy. Herein, we demonstrate that prolonged cytokine stimulation combined with metabolic restriction, through inhibition of mTORC1, is sufficient to induce persistent dysfunction in human NK cells. TGFβ, also restricted NK cell metabolism and promoted persistent NK cell dysfunction. NK cells from patients with metastatic breast cancer had profound metabolic defects in glycolysis and mitochondrial function, and clear structural differences in NK cell mitochondrial morphology. Importantly, blocking elevated TGFβ improved readouts of metabolism and restored IFNγ production in patient NK cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.