Based on: Metabolic reprogramming of natural killer cells in obesity limits antitumor responses
by Michelet et al.
Published November 12, 2018
PI: Lydia Lynch - link to this page
A recent major discovery in the field of immunology points to mechanisms underlying the link between obesity and cancer, largely connected to the immune response led by Natural Killer (NK) cells. Under normal circumstances, the immune system recognizes and successfully fights cancerous cells, but when cancer thrives, it is usually because the immune system has failed (1). When that process breaks down, tumors form via various pathways (1). Cancer cells are born out of genetic variation such as mutations or rearrangement of pieces of different chromosomes (2). Because of that, essentially all cancers have new foreign genes, so that host T cells are generally able to detect tumor antigens (2). However, there is a well documented correlation between cancer and obesity, with up to 49% of certain types of cancers attributed to obesity (3). Over 1.9 billion adults are overweight and obese, making up over one third of the world’s population (2). Until now, however, little has been understood about the impact of obesity on immune surveillance (4). This new study by Michelet et al. has confirmed that the immune response led by cancer-fighting NK cells fails in the presence of excess fat (3). It also outlines new treatment strategies for the reprogramming of “fat-clogged” NK cells to essentially reactivate them (3).
NK cells are central to the innate immune system that is typically responsible for tumor suppression (5). They destroy their targets by secreting cytotoxic granules that include perforin and apoptosis-inducing granzymes (5). NK cells require a greater amount of energy to support anti-tumor activity, meaning that they must switch their metabolic activity from oxidative phosphorylation to glycolysis to meet an increased demand for ATP (3).
Figure 1. Summary of NK cell role in the innate immune response. Image taken from Gardiner & Finlay (2017). The major innate cytokines that activate NK cells are IL-12, IL-15, and IL-18 (11). NK cells carry out direct cytotoxicity of target cells and are potent producers of IFNγ (11). IL-2 is the cytokine that drives mTORC1-dependent glycolytic reprogramming of NK cells (11).
The authors on this paper worked with natural killer cells from humans as well as mice, which serve as valuable model organisms because their genetic, biological and behavioral characteristics resemble that of humans (3). Their first discovery was that the presence of excess fat clogs up the lytic machinery of NK cells by inducing lipid metabolism. That lipid accumulation affects their cellular energetics, resulting in “metabolic paralysis” (3), which is what leads to the eventual loss of anti-tumor function. In order to better understand the effects that obesity has, they examined mouse models of diet-induced obesity (3), performing transcriptional analysis to see how NK expression varied in mice with a high-fat versus a control diet (3). They found that the high fat diet led to a substantial upregulation of lipid handling and metabolizing genes in the NK cells. Those results suggest that obesity induces metabolic reprogramming in NK cells to lipid metabolism, which inhibits the expression of effector molecules that would be important in an innate immune response (3). Additionally, they found a significantly reduced number of high lipid content NK cells when comparing obese and lean individuals, which was consistent with previous studies (6). There was an accompanying loss of NK cell function in humans with presence of excess fat, as they had previously found in mice (3).
In examining the mechanisms underlying these alterations to NK function, researchers found that the mTOR (mammalian target of rapamycin) pathway was inhibited in obesity (3). This pathway is extremely important in regulation of the cell cycle (7). mTORC1 (the molecule of focus in this study) can be activated by diverse stimuli including growth factors, nutrients, energy and stress signals, and other essential signaling pathways (7). One of its main functions is to activate proteins that are important to RNA translation (7), though its most important role is as a regulator that controls cell growth, proliferation and survival (8). mTORC1 activation is crucial for NK cell function, particularly IFN-γ production (3). The researchers treated human NK cells with rapamycin, the main inhibitor of this pathway, and found that tumor-killing was greatly reduced in rapamycin-treated cells (3). Understanding the importance of the mTOR pathway in anti-tumor activity, they then examined mTOR’s response to lipid accumulation and the data indicated that mTORC1 activation was greatly reduced in obese individuals (3). Those findings confirm that inhibition of the mTOR pathway in response to lipid accumulation is a major mechanism for reduced tumor-suppressing activity of NK cells.
The study looked into another pathway important in NK cell function: the PPARα/δ pathway, which is linked to lipid metabolic pathways (9). The study found that PPAR target gene expression increased in mice and human obesity (3). Interestingly, they found that the PPAR pathway led to increased lipid uptake and inhibition of the previously mentioned mTOR pathway. When tested in mice, PPARα/δ agonists mimicked the effects of obesity on NK cell function (3).
One of the most interesting findings of the study was the reversibility of the metabolic defects in NK cells associated with excess fat (3). Researchers found that blocking Cpt1, a gene that is upregulated in obesity and involves transportation of fatty acids to the mitochondria, increased glycolysis by inducing a switch from oxidative phosphorylation (3). While both glycolysis and oxidative phosphorylation were defective in obesity, previous studies had demonstrated the importance of glycolysis in NK cell function (10). Therefore, they reasoned that increasing glycolysis would restore the cytotoxicity of NK cells (3). Both glycolysis increase and NK cell cytotoxicity was restored when they introduced the Cpt1 inhibitor etomoxir (3).
The researchers were able to mimic obesity through lipid administration and by using PPARα/δ agonists, which inhibit mechanistic target of rapamycin (mTOR)-mediated glycolysis (3). In other words, they found that the both those pathways were important to the NK cell defects in obesity. They used this to find that it was possible to reverse the harmful metabolic paralysis by (a) inhibiting PPARα/δ or blocking lipid transport (3). All of that suggests that metabolic reprogramming of NK cells could restore their anti-tumor activity in cases of human obesity (3), suggesting exciting new possibilities for antitumor therapies.
It is well documented that obesity is associated with immune dysregulation, but most studies have focused on other pathways associated with inflammation that interferes with insulin signaling and contributes to diabetes (2). This recently published study contributes knew knowledge of how obesity also impairs antitumor activity of the immune system.
References
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3. Michelet, X., Dyck, L., Hogan, A., Loftus, R. M., Duquette, D., Wei, K., O’Farrelly, C. (2018). Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nature immunology, https://www.nature.com/articles/s41590-018-0251-7.pdf
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11. Gardiner, C. M., & Finlay, D. K. (2017). What fuels natural killers? Metabolism and NK cell responses. Frontiers in immunology, 8: 367.
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