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Metabolic reprogramming of natural killer cells in obesity limits antitumor responses

Nature Immunology volume 19, pages 1330–1340 (2018)Cite this article

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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.

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Fig. 1: NK cells from HFD mice show upregulation of lipid metabolism-related genes and downregulation of the killing machinery.
Fig. 2: Obesity leads to NK cell loss of function and lipid accumulation.
Fig. 3: Lipid uptake and accumulation leads to NK cell loss of function.
Fig. 4: Lipid accumulation during obesity impairs mTOR pathway.
Fig. 5: Lipid accumulation during obesity negatively impacts NK cell metabolism.
Fig. 6: Activation of the PPARα/δ pathway induces functional and metabolic defects in NK cells.
Fig. 7: The decreased ability of NK cells to kill tumor cells in obesity is related to a defect of lytic granule polarization and can be reversed with metabolic reprograming.
Fig. 8: Lipid uptake reduces NK cell antitumor activity in vivo.

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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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Author notes

  1. These authors contributed equally: Xavier Michelet, Lydia Dyck, Lydia Lynch.

Authors and Affiliations

  1. Brigham and Women’s Hospital, Boston, MA, USA

    Xavier Michelet, Danielle Duquette, Kevin Wei, Ali Tavakkoli, Ashley Vernon, William Pettee, Michael B. Brenner & Lydia Lynch

  2. Harvard Medical School, Boston, MA, USA

    Xavier Michelet, Semir Beyaz, Michael B. Brenner & Lydia Lynch

  3. School of Biochemistry and Immunology & School of Medicine, Trinity College Dublin, Dublin, Ireland

    Lydia Dyck, Roisin M. Loftus, Cathriona Foley, Raymond Donnelly, Cliona O’Farrelly, Mathilde Raverdeau, Kingston H. G. Mills, David Finlay & Lydia Lynch

  4. Human Health Institute Maynooth University, Kildare, Ireland

    Andrew Hogan & Donal O’Shea

  5. Education Research Centre, St. Vincent’s University Hospital, Dublin, Ireland

    Donal O’Shea

  6. Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY, USA

    Barbara S. Nikolajczyk

  7. School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland

    David Finlay

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Contributions

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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Correspondence to Lydia Lynch.

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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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