Metabolic reprogramming of natural killer cells in obesity limits antitumor responses

Abstract

ore than 1.9 billion adults are overweight or obese, representing over one third of the worldwide adult population 1. The biggest health and economic burden of obesity is the large number of obesity-related co-morbidities. In addition to type 2 diabetes and cardiovascular disease, obesity is associated with an increased risk of cancer and infections 2-4. Indeed, up to 49% of certain types of cancer are now attributed to obesity 3 , and weight loss through bariatric surgery can reverse cancer risk 5. Potential mechanisms for the increased risk of cancer associated with obesity include overproduction of hormones (for example, oestrogens), adipokines (for example, leptin), and insulin, which favor cell proliferation and tumor growth 6,7. Peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of cellular metabolism. It has recently been shown that obesity induces a PPAR-driven lipid metabolism program in metastatic tumor cells, which enhances metastasis and tumor cell survival 8. In intestinal stem cells, obesitydriven PPAR signaling enhances stemness and tumor progression 9. However, despite the increasing attention to the role of the immune system and inflammation in obesity-driven insulin resistance, the impact of obesity-induced dysfunction on immunosurveillance and cancer risk is not well understood. Natural killer (NK) cells have crucial roles in protective immunity against tumors and viral infections 10. NK cells kill their targets through the directed secretion of lytic granules, which contain pore-forming perforin and apoptosis-inducing granzymes 11-13. Cellular metabolism has a critical role in the function of immune cells. NK cells switch the balance of the core metabolic program from oxidative phosphorylation (OXPHOS) to glycolysis to meet the increased energy required to kill tumor cells 14,15 , although the steps in the killing process that require this metabolic activation are unknown. Humans and mice with obesity display numerical and functional defects in NK cells and have an increased risk of cancer and infections. As obesity is a state of altered metabolism, we investigated the effect of obesity on the cellular metabolism, gene expression, and function of NK cells, and its contribution to cancer development. Our data show that NK cell uptake of lipids from the environment in human obesity interfered with their cellular bioenergetics, inducing 'metabolic paralysis'. Lipid-induced metabolic defects caused NK cell incompetence by inhibiting trafficking of the cytotoxic machinery, leading to loss of antitumor functions in vitro and in vivo. Our data suggest that obesity targets immunometabolic pathways and that this may be partly responsible for the increased cancer and infection risks in obesity, and suggest that metabolic reprogramming may improve innate immunosurveillance in obesity. Results Obesity induces lipid metabolism in NK cells. To better understand the effects of obesity on NK cells, we examined mouse models of diet-induced obesity. We performed transcriptional a...

Immunometabolism: From basic mechanisms to translation

“…86 Obesity alters not just Treg, but also CD4 and CD8 T cells that play roles in anti-tumor immunity. 87,88 Adipokines, such as leptin, are elevated in obese individuals and can promote T cell glycolysis and polarization toward an anti-tumor Th1 phenotype. 89 cells.…”

Obesity and CD8 T cell metabolism: Implications for anti‐tumor immunity and cancer immunotherapy outcomes

“…133 In NK cells, elevated CD36 expression and intracellular lipid accumulation were associated with impaired IFNγ secretion, diminished cytolytic capacity, and NK failure to control a melanoma tumor challenge. 131 These detrimental effects of the obese host environment were linked specifically to elevated levels of free fatty acids, as administration of palmitate or PPAR agonists impaired glucose uptake and both glycolysis and OXPHOS in splenic NK cells examined ex vivo. Of note, NK metabolic and effector dysfunction induced by palmitate could be reversed by administration of etomoxir, an inhibitor of Cpt1b and fatty acid oxidation.…”

“…In addition, future preclinical studies also will need to examine the individual vs combined impact of various facets of host obesity on the metabolic profiles and effector functions of CD8 TILs, as in the exogenous palmitate addition studies we summarized above. 69,131 These studies will again need to be conducted using tumors that arise in different anatomic locations, in the presence vs absence of immune checkpoint inhibitors or other therapies of interest.…”

NK cell metabolism

“…51 Similar impaired cytotoxicity was recently found using NK cells from obese adult's mice fed on a high fat diet. 52 Impaired trafficking of cytotoxicity machinery to the NK cell synapse was identified as a mechanism that contributed to this phenotype.…”