Michelet, Dyck, and Lynch et al. demonstrate that in human and murine obesity, in which free fatty acids are elevated in circulation, NK cells take up lipids, triggering upregulation of PPARα/δ transcription factors and their target genes which control lipid metabolism. This in turn inhibits the mTOR pathway, leading to impaired glycolysis, reduced expression of granzymes, perforin, and IFNγ, and inability to traffick lytic granules to the NK cell-tumor synapse. In vivo, obesity in mice led to reduced tumor control. Blocking the transport of fatty acids to mitochondria or inhibiting PPARα/δ restored glycolysis and the cytotoxic capacity of NK cells.

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 PPARalpha and PPARdelta (PPARalpha/delta) 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 PPARalpha/delta 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.

Author Info: (1) Brigham and Women's Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (2) School of Biochemistry and Immunology & School of Medicine, Trinity

Author Info: (1) Brigham and Women's Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (2) School of Biochemistry and Immunology & School of Medicine, Trinity College Dublin, Dublin, Ireland. (3) Human Health Institute Maynooth University, Kildare, Ireland. (4) School of Biochemistry and Immunology & School of Medicine, Trinity College Dublin, Dublin, Ireland. (5) Brigham and Women's Hospital, Boston, MA, USA. (6) Brigham and Women's Hospital, Boston, MA, USA. (7) Harvard Medical School, Boston, MA, USA. (8) Brigham and Women's Hospital, Boston, MA, USA. (9) School of Biochemistry and Immunology & School of Medicine, Trinity College Dublin, Dublin, Ireland. (10) School of Biochemistry and Immunology & School of Medicine, Trinity College Dublin, Dublin, Ireland. (11) School of Biochemistry and Immunology & School of Medicine, Trinity College Dublin, Dublin, Ireland. (12) School of Biochemistry and Immunology & School of Medicine, Trinity College Dublin, Dublin, Ireland. (13) Brigham and Women's Hospital, Boston, MA, USA. (14) Brigham and Women's Hospital, Boston, MA, USA. (15) Human Health Institute Maynooth University, Kildare, Ireland. Education Research Centre, St. Vincent's University Hospital, Dublin, Ireland. (16) Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY, USA. (17) School of Biochemistry and Immunology & School of Medicine, Trinity College Dublin, Dublin, Ireland. (18) Brigham and Women's Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (19) School of Biochemistry and Immunology & School of Medicine, Trinity College Dublin, Dublin, Ireland. School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. (20) Brigham and Women's Hospital, Boston, MA, USA. llynch@bwh.harvard.edu. Harvard Medical School, Boston, MA, USA. llynch@bwh.harvard.edu. School of Biochemistry and Immunology & School of Medicine, Trinity College Dublin, Dublin, Ireland. llynch@bwh.harvard.edu.

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