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

doi:10.1038/s41590-018-0251-7

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 journal › Article › peer-review

518 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 language	English
Pages (from-to)	1330-1340
Number of pages	11
Journal	Nature Immunology
Volume	19
Issue number	12
DOIs	https://doi.org/10.1038/s41590-018-0251-7
State	Published - Dec 1 2018

Bibliographical note

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

Funding

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.).

Funders	Funder number
Cancer Research Institute CLIP	16/FRL/3865
National Institutes of Health (NIH)	R01 AI11304603
National Institutes of Health (NIH)
Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases	R01AI134861
Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases
H2020 European Research Council	679173
H2020 European Research Council

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41590-018-0251-7

Cite this

Michelet, X., Dyck, L., Hogan, A., Loftus, R. M., Duquette, D., Wei, K., Beyaz, S., Tavakkoli, A., Foley, C., Donnelly, R., O’Farrelly, C., Raverdeau, M., Vernon, A., Pettee, W., O’Shea, D., Nikolajczyk, B. S., Mills, K. H. G., Brenner, M. B., Finlay, D., & Lynch, L. (2018). Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nature Immunology, 19(12), 1330-1340. https://doi.org/10.1038/s41590-018-0251-7

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title = "Metabolic reprogramming of natural killer cells in obesity limits antitumor responses",

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 {\textquoteleft}paralysis{\textquoteright} 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.",

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

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2018",

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doi = "10.1038/s41590-018-0251-7",

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Michelet, X, Dyck, L, Hogan, A, Loftus, RM, Duquette, D, Wei, K, Beyaz, S, Tavakkoli, A, Foley, C, Donnelly, R, O’Farrelly, C, Raverdeau, M, Vernon, A, Pettee, W, O’Shea, D, Nikolajczyk, BS, Mills, KHG, Brenner, MB, Finlay, D & Lynch, L 2018, 'Metabolic reprogramming of natural killer cells in obesity limits antitumor responses', Nature Immunology, vol. 19, no. 12, pp. 1330-1340. https://doi.org/10.1038/s41590-018-0251-7

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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

PY - 2018/12/1

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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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VL - 19

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JO - Nature Immunology

JF - Nature Immunology

IS - 12

ER -

Metabolic reprogramming of natural killer cells in obesity limits antitumor responses

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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