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.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
We thank M. Wilk and J. Barrett for assistance with experiments. This research was supported by National Institutes of Health (NIH) grant R01 AI11304603 (M.B.B.), European Research Council (ERC) Starting Grant 679173, a Cancer Research Institute CLIP grant and 16/FRL/3865 (L.L.).
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X.M., L.D., and L.L. conceived and designed the experiments, and wrote the manuscript. X.M., L.D., A.H., R.M.L., D.D., K.W., R.D., M.R., and L.L. performed the experiments. C.F. performed the RNA-seq analysis. A.T., A.V., W.P., D.O.’S., and B.S.N. obtained patient samples and coordinated the clinical investigations. S.B., C.O.F., K.H.G.M., M.B.B., and D.F. provided advice, reagents and critical insight.
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Michelet, X., Dyck, L., Hogan, A. et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat Immunol 19, 1330–1340 (2018). https://doi.org/10.1038/s41590-018-0251-7
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DOI: https://doi.org/10.1038/s41590-018-0251-7
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