University of Dundee

"Obesity prevents NK cell cytotoxicity and promotes tumor progression"

Event Date: 
Wednesday, May 16, 2018 - 13:00
Event Location: 
CTIR Sir Kenneth and Lady Noreen Murray Seminar Room
Professor Simon Arthur
Event Speaker: 
Professor Lydia Lynch
Trinity College Dublin
Event Type: 
All Welcome

Up to 50% of certain cancers are now attributed to obesity and potential mechanisms include overproduction of hormones, adipokines, and insulin, which favor tumor cell growth. Obesity also induces PPAR-driven lipid metabolism in tumor cells, which fuels their proliferation and metastasis. Cytotoxic immune cells including NK cells and CD8 T cells play an important role in tumor surveillance, but little is known about the impact of obesity on immune surveillance and its role in cancer risk in obesity. Here we show that obesity induces a robust PPAR-driven lipid accumulation in NK cells in humans and mice, causing complete ‘paralysis’ in their cellular metabolism and cellular trafficking. Fatty acid treatment, and PPARa/d agonists, mimicked obesity and inhibited mTor-mediated glycolysis. This prevented the traffic of cytotoxic machinery to the NK:tumor synapse, which is essential for tumor death. Inhibiting PPARa/d or blocking transport of lipids into the mitochondria reversed NK cell metabolic paralysis and restored their cytotoxic function.  In vivo, lipid-treated NK cells had a blunted anti-tumor response and failed to reduce tumor growth. Our results demonstrate that the lipotoxic obese environment impairs immune surveillance and suggests that metabolic reprogramming of NK cells may improve cancer and infection outcomes in obesity.