Metabolic reprogramming of natural killer cells in obesity limits antitumor responses

Xavier Michelet, Lydia Dyck, Andrew Hogan, Roisin M. Loftus, Danielle Duquette, Kevin Wei, Semir Beyaz, Ali Tavakkoli, Cathriona Foley, Raymond Donnelly, Cliona O’Farrelly, Mathilde Raverdeau, Ashley Vernon, William Pettee, Donal O’Shea, Barbara S. Nikolajczyk, Kingston H.G. Mills, Michael B. Brenner, David Finlay, Lydia Lynch

Research output: Contribution to journalArticlepeer-review

371 Scopus citations

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.

Original languageEnglish
Pages (from-to)1330-1340
Number of pages11
JournalNature Immunology
Volume19
Issue number12
DOIs
StatePublished - Dec 1 2018

Bibliographical note

Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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