TY - JOUR
T1 - Metabolic reprogramming of natural killer cells in obesity limits antitumor responses
AU - Michelet, Xavier
AU - Dyck, Lydia
AU - Hogan, Andrew
AU - Loftus, Roisin M.
AU - Duquette, Danielle
AU - Wei, Kevin
AU - Beyaz, Semir
AU - Tavakkoli, Ali
AU - Foley, Cathriona
AU - Donnelly, Raymond
AU - O’Farrelly, Cliona
AU - Raverdeau, Mathilde
AU - Vernon, Ashley
AU - Pettee, William
AU - O’Shea, Donal
AU - Nikolajczyk, Barbara S.
AU - Mills, Kingston H.G.
AU - Brenner, Michael B.
AU - Finlay, David
AU - Lynch, Lydia
N1 - Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41590-018-0251-7
DO - 10.1038/s41590-018-0251-7
M3 - Article
C2 - 30420624
AN - SCOPUS:85056602852
SN - 1529-2908
VL - 19
SP - 1330
EP - 1340
JO - Nature Immunology
JF - Nature Immunology
IS - 12
ER -