Metabolic reprogramming of natural killer cells in obesity limits antitumor responses
| Autor: | Xavier Michelet, Róisín M. Loftus, Kingston H. G. Mills, Danielle Duquette, Andrew E. Hogan, Lydia Lynch, Barbara S. Nikolajczyk, Michael B. Brenner, Lydia Dyck, Cliona O'Farrelly, Cathriona Foley, Ashley H. Vernon, David K. Finlay, William Pettee, Raymond P. Donnelly, Kevin Wei, Ali Tavakkoli, Semir Beyaz, Mathilde Raverdeau, Donal O'Shea |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Immunology Melanoma Experimental Peroxisome proliferator-activated receptor Mice Young Adult 03 medical and health sciences Immune system Animals Humans Immunology and Allergy Cytotoxic T cell Obesity Receptor Immunologic Surveillance Mechanistic target of rapamycin PI3K/AKT/mTOR pathway chemistry.chemical_classification biology Middle Aged 3. Good health Killer Cells Natural Mice Inbred C57BL Immunosurveillance 030104 developmental biology chemistry Cancer research biology.protein Female CD8 |
| Zdroj: | Nature Immunology |
| ISSN: | 1529-2916 1529-2908 |
| DOI: | 10.1038/s41590-018-0251-7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink