Michelet, Xavier and Dyck, Lydia and Hogan, Andrew E. and Loftus, Roisin and Duquette, Danielle and Wei, Kevin and Beyaz, Semir and Tavakkoli, Ali and Foley, Cathriona and Donnelly, Raymond and O'Farrelly, Cliona and Raverdeau, Mathilde and Veron, Ashley and Pettee, William and O'Shea, Donal and Nikolajczyk, Barbara S and Mills, Kingston H.G. and Brenner, Michael B. and Finlay, David and Lynch, Lydia (2018) Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nature Immunology, 19. pp. 1330-1340. ISSN 1529-2908

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Abstract

Up to 49% of certain types of cancer are attributed to obesity, and potential mechanisms include overproduction of hormones, adipokines, and insulin. Cytotoxic immune cells, including natural killer (NK) cells and CD8+ T cells, are important in tumor surveillance, but little is known about the impact of obesity on immunosurveillance. Here, we show that obesity induces robust peroxisome proliferator-activated receptor (PPAR)-driven lipid accumulation in NK cells, causing complete ‘paralysis’ of their cellular metabolism and trafficking. Fatty acid administration, and PPARα and PPARδ (PPARα/δ) agonists, mimicked obesity and inhibited mechanistic target of rapamycin (mTOR)-mediated glycolysis. This prevented trafficking of the cytotoxic machinery to the NK cell–tumor synapse. Inhibiting PPARα/δ or blocking the transport of lipids into mitochondria reversed NK cell metabolic paralysis and restored cytotoxicity. In vivo, NK cells had blunted antitumor responses and failed to reduce tumor growth in obesity. Our results demonstrate that the lipotoxic obese environment impairs immunosurveillance and suggest that metabolic reprogramming of NK cells may improve cancer outcomes in obesity.

Item Type:	Article
Keywords:	Metabolic; reprogramming; natural killer cells; obesity; limits; antitumor responses;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	13238
Identification Number:	https://doi.org/10.1038/s41590-018-0251-7
Depositing User:	Andrew Hogan
Date Deposited:	17 Sep 2020 10:57
Journal or Publication Title:	Nature Immunology
Publisher:	Nature Publishing Group
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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