Abstract
The control of cellular metabolism is now recognized as key to regulate functional properties of immune effectors such as T or Natural Killer (NK) cells. During persistent infections or in the tumor microenvironment, multiple metabolic changes have been highlighted in T cells that contribute to their dysfunctional state or exhaustion. NK cells may also undergo major phenotypic and functional modifications when infiltrating tumors that could be linked to metabolic alterations. The mammalian target of rapamycin (mTOR) kinase is a central regulator of cellular metabolism. mTOR integrates various extrinsic growth or immune signals and modulates metabolic pathways to fulfill cellular bioenergetics needs. mTOR also regulates transcription and translation thereby adapting cellular pathways to the growth or activation signals that are received. Here, we review the role and regulation of mTOR in NK cells, with a special focus on cytokines that target mTOR such as IL-15 and TGF-β. We also discuss how NK cell metabolic activity could be enhanced or modulated to improve their effector anti-tumor functions in clinical settings.
Highlights
Natural killer (NK) cells are Innate Lymphoid Cells (ILCs) able to kill abnormal cells recognized as targets and to produce large amounts of IFN-γ and other cytokines and chemokines upon activation [1].This allows them to take part in the immuno-surveillance of cancers [1]
A recent study investigating the relative effect of IL-2 and IL-15 in in vitro treatment described a better persistence of IL-15 effects on Natural Killer (NK) cells anti-tumor functions upon cytokine withdrawal [21]
We observed that TGF-β inhibits mammalian target of rapamycin (mTOR) signaling and has similar effects as those induced by the mTORC1 specific inhibitor rapamycin on NK cell metabolism
Summary
Natural killer (NK) cells are Innate Lymphoid Cells (ILCs) able to kill abnormal cells recognized as targets and to produce large amounts of IFN-γ and other cytokines and chemokines upon activation [1] This allows them to take part in the immuno-surveillance of cancers [1]. Improving bioenergetics by overexpression of PGC-1α may enhance function in exhausted T cells, both in cancer and infection settings. Whether this is the case for NK cells requires further investigation but multiple recent articles reported that several cytokines may control NK cell metabolism by regulating the activity of the mTOR kinase. We review the corresponding literature and discuss how metabolic activity could be reinvigorated in NK cells to enhance their anti-tumor activity
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