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

Producción científica: Article › revisión exhaustiva

548 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	1330-1340
Número de páginas	11
Publicación	Nature Immunology
Volumen	19
N.º	12
DOI	https://doi.org/10.1038/s41590-018-0251-7
Estado	Published - dic 1 2018

Nota bibliográfica

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

Financiación

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.).

Financiadores	Número del financiador
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

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1038/s41590-018-0251-7

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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

@article{2d156a1baf6c4af7bae86916f2882764,

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",

month = dec,

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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, n.º 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

Y1 - 2018/12/1

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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UR - https://www.scopus.com/pages/publications/85056602852#tab=citedBy

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M3 - Article

C2 - 30420624

AN - SCOPUS:85056602852

SN - 1529-2908

VL - 19

SP - 1330

EP - 1340

JO - Nature Immunology

JF - Nature Immunology

IS - 12

ER -

Metabolic reprogramming of natural killer cells in obesity limits antitumor responses

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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