Obesity and Cancer: ‘Fat-clogged’ Immune Cells Fail to Fight Tumors
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Researchers have gained a new understanding of the link between obesity and cancer. In the presence of excess fat, the immune surveillance system fails due to an obesity-fueled lipid accumulation in natural killer (NK) cells, preventing their cellular metabolism and trafficking. The new findings were published in Nature Immunology.1
More than 1.9 billion adults are either overweight or obese and a growing amount of evidence proposes that numerous cancer types (including liver, kidney, endometrial and pancreatic cancers)2 are more common in overweight or obese people. Cancer risk is increased in those with higher body fat, with up to 49% of certain types attributed to obesity.3
Previous findings from the GLOBOCAN project indicate that, in 2012 in the United States, approximately 28,000 new cases of cancer in men and approximately 72,000 in women were associated with being obese or overweight.4
The 2018 study1 investigated the effect of obesity on the cellular metabolism, gene expression, and function of NK cells, and its influence on cancer development.
NK cells are cells of the innate immune system that limit the spread of tumors – numerous in vitro models have shown that tumor cells are recognized as ‘targets’ by NK cells.5 These cells destroy their targets by secreting lytic granules containing perforin and apoptosis-inducing granzymes. NK cells require a greater amount of energy to support their anti-tumor activity, therefore they switch their metabolic activity from oxidative phosphorylation (OXPHOS) to glycolysis to meet the increased demand for ATP.1
The researchers discovered that NK cells in an ‘obese environment’ display increased lipid accumulation which affects their cellular bioenergetics, resulting in ‘metabolic paralysis’. This lipid-induced metabolic paralysis led to loss of anti-tumor activity both in vitro and in vivo models. They were able to mimic obesity through fatty-acid administration and by using PPARα/δ agonists, which inhibited mechanistic target of rapamycin (mTOR)-mediated glycolysis.1
However, the researchers also discovered that it was possible to reverse the metabolic paralysis by either inhibiting PPARα/δ or by blocking lipid transport, suggesting that metabolic reprogramming of NK cells could restore their anti-tumor activity in human obesity.1
Corresponding author of the study, Lydia Lynch commented on the importance of the findings in a recent press release: “Despite increased public awareness, the prevalence of obesity and related diseases continue. Therefore, there is increased urgency to understand the pathways whereby obesity causes cancer and leads to other diseases, and to develop new strategies to prevent their progression."
References
1. Michelet, X., et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nature Immunology. (2018) https://www.nature.com/articles/s41590-018-0251-7
2. Mason, L. E., The Link Between Cancer and Obesity. Technology Networks. Available at: https://www.technologynetworks.com/cancer-research/articles/the-link-between-cancer-and-obesity-298207. Accessed: November 12, 2018
3. Renehan, A. G., et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. (2008) 371, 569–578
4. Arnold, M., et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol. (2015) 16(1): 36–46
5. Vivier, E., et al. Functions of natural killer cells. Nature Immunology. (2008) 9, 503–510
