NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient

Tobin, Laura; Mavinkurve, Meenal; Carolan, Eirin; Kinlen, David; O'Brien, Eóin C; Little, Mark A.; Finlay, David K.; Cody, Declan; Hogan, Andrew E.; O’Shea, Donal

doi:10.1172/jci.insight.94939

Cited by 91 publications

(111 citation statements)

References 32 publications

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“…However, their functions were severely diminished and NK cells did not upregulate immune responses normally upon cytokine stimulation. They appeared to become exhausted much more rapidly upon activation than NK cells from lean children . Similar impaired cytotoxicity was recently found using NK cells from obese adult's mice fed on a high fat diet .…”

Section: What About Nk Cell Metabolism?supporting

confidence: 76%

“…They appeared to become exhausted much more rapidly upon activation than NK cells from lean children. 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.…”

Section: Altered Nk Cell Metabolism In Diseasesupporting

confidence: 71%

“…NK cell metabolism has been less well‐studied but is likely to significantly contribute to the immune dysfunction observed in these particular diseases. One recent article has described how NK cells from obese children are metabolically dysregulated . This included increased glycolysis, mROS, basal mTORC1 activity, and nutrient receptor expression in freshly isolated cells.…”

Section: What About Nk Cell Metabolism?mentioning

confidence: 99%

“…One recent article has described how NK cells from obese children are metabolically dysregulated. 51 This included increased glycolysis, mROS, basal mTORC1 activity, and nutrient receptor expression in freshly isolated cells. However, their functions were severely diminished and NK cells did not upregulate immune responses normally upon cytokine stimulation.…”

Section: Altered Nk Cell Metabolism In Diseasementioning

confidence: 99%

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NK cell metabolism

Gardiner

2019

Journal of Leukocyte Biology

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Natural Killer (NK) cells are important antiviral and anticancer effector cells. They have excellent potential for immunotherapy although impaired functions during cancer limit their effectiveness. The discovery that cellular metabolism can impact on and regulate immune functions has led to an explosion of articles in this new area of immunometabolism. Metabolism has recently been shown to impact both murine and human NK cell biology. This review is targeted for newcomers to the field; it will introduce basic concepts in the area of immunometabolism including key aspects of glucose metabolism and mitochondrial function. It will review our current understanding of how metabolism of NK cells is differentially impacted in a variety of important situations. This is a rapidly expanding and exciting area of research that holds great potential for improving NK cell‐based immunotherapies.

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Section: What About Nk Cell Metabolism?supporting

confidence: 76%

Section: Altered Nk Cell Metabolism In Diseasesupporting

confidence: 71%

Section: What About Nk Cell Metabolism?mentioning

confidence: 99%

Section: Altered Nk Cell Metabolism In Diseasementioning

confidence: 99%

See 2 more Smart Citations

NK cell metabolism

Gardiner

2019

Journal of Leukocyte Biology

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“…It is becoming increasingly apparent that NK cells are dysfunctional in obesity (O'Shea et al, 2010;Tobin et al, 2017;Michelet et al, 2018), and that this could be one mechanism that accounts for the link between obesity and cancer (Michelet et al, 2018). These studies have largely focused on Fig.…”

Section: Discussionmentioning

confidence: 99%

TGFβ in the obese liver mediates conversion of NK cells to a less cytotoxic ILC1-like phenotype

Cuff

Sillito

Dertschnig

et al. 2019

Preprint

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The liver contains both NK cells and their less cytotoxic relatives, ILC1. Here, we investigate the role of NK cells and ILC1 in the obesity-associated condition, non-alcoholic fatty liver disease (NAFLD). In the livers of mice suffering from NAFLD, NK cells are less able to degranulate, express lower levels of perforin and are less able to kill cancerous target cells than those from healthy animals. This is associated with a decreased ability to kill cancer cells in vivo. On the other hand, we find that perforin-deficient mice suffer from less severe NAFLD, suggesting that this reduction in NK cell cytotoxicity may be protective in the obese liver, albeit at the cost of increased susceptibility to cancer. The decrease in cytotoxicity is associated with a shift towards a transcriptional profile characteristic of ILC1, increased expression of the ILC1-associated proteins CD200R1 and CD49a, and an altered metabolic profile mimicking that of ILC1. We show that the conversion of NK cells to this less cytotoxic phenotype is at least partially mediated by TGFβ, which is expressed at high levels in the obese liver. Finally, we show that reduced cytotoxicity is also a feature of NK cells in the livers of human NAFLD patients.

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Mechanisms of NK cell dysfunction in the tumor microenvironment and current clinical approaches to harness NK cell potential for immunotherapy

Devillier

Chrétien

Pagliardini

et al. 2020

Journal of Leukocyte Biology

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NK cells are innate immune cells with inherent capabilities in both recognizing and killing cancer cells. NK cell phenotypes and functional alterations are being described with increasing precision among patients harboring various cancer types, emphasizing the critical role that NK cells play in antitumor immune responses. In addition, advances in understanding NK cell biology have improved our knowledge of such alterations, thereby expanding the potential exploitation of NK cells' anticancer capabilities. In this review, we present an overview of (1) the various types of NK cell alterations that may contribute to immune evasion in cancer patients and (2) the various strategies to improve NK cell-based anticancer immunotherapies, including pharmacologic modulation and/or genetic modification.

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NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient

Cited by 91 publications

References 32 publications

NK cell metabolism

NK cell metabolism

TGFβ in the obese liver mediates conversion of NK cells to a less cytotoxic ILC1-like phenotype

Mechanisms of NK cell dysfunction in the tumor microenvironment and current clinical approaches to harness NK cell potential for immunotherapy

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