Srebp-controlled glucose metabolism is essential for NK cell functional responses

Aßmann, Nadine; O’Brien, Katie; Donnelly, Raymond P.; Dyck, Lydia; Zaiatz-Bittencourt, Vanessa; Loftus, Róisín M; Heinrich, P; Oefner, Peter J.; Lynch, Lydia; Gardiner, Clair M.; Dettmer, Katja; Finlay, David K.

doi:10.1038/ni.3838

Cited by 279 publications

(308 citation statements)

References 57 publications

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“…A new metabolic pathway was recently revealed by 13 C 6 ‐glucose metabolomics analysis of murine NK cells activated by cytokine (see Fig. ) . While glycolysis was a key pathway for glucose usage as expected (consumed ∼80% of the glucose), only low activity of the TCA cycle was recorded.…”

Section: What About Nk Cell Metabolism?mentioning

confidence: 62%

“…mTORC1 also regulates many other immune functions and while changes in metabolism correlate well with functional changes, NK cell‐specific deletions of key metabolic genes will be required to definitively address the specific role of metabolism in regulating NK cell functions. However, other important regulators are beginning to be discovered, for example, the transcription factor, Srebp, which regulates Oxphos in murine NK cells as previously mentioned . The transcriptional regulator, ARID5B, found to be differentially expressed between canonical and adaptive NK cells, was shown (using NK‐92 cell line) to promote several aspects of NK cell metabolism including MMP, transcription of genes encoding ETC components, and Oxphos .…”

Section: What About Nk Cell Metabolism?mentioning

confidence: 95%

“…While glycolysis was a key pathway for glucose usage as expected (consumed ∼80% of the glucose), only low activity of the TCA cycle was recorded. Rather, NK cells exported citrate from the mitochondria and generated fuels for the ETC and Oxphos using a biochemical shuttle (the citrate malate shuttle) that is more commonly identified as playing a role in lipid synthesis . How and why this pathway is used rather than the TCA cycle remains to be explored.…”

Section: What About Nk Cell Metabolism?mentioning

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?mentioning

confidence: 62%

Section: What About Nk Cell Metabolism?mentioning

confidence: 95%

Section: What About Nk Cell Metabolism?mentioning

confidence: 99%

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NK cell metabolism

Gardiner

2019

Journal of Leukocyte Biology

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“…Metabolism is strongly linked with immunity . The differentiation and function of immune cells large depend on metabolic regulation . The synthesis and degradation of glucose, amino acids, and FA can supply energy for immune cells to meet the high energy demand .…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rh2 reverses cyclophosphamide-induced immune deficiency by regulating fatty acid metabolism

Qian

Huang

et al. 2019

Journal of Leukocyte Biology

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Ginsenoside Rh2 (G‐Rh2) has well‐established potent antitumor activity; yet, the effects of G‐Rh2 on immune and metabolism regulation in cancer treatment, especially non‐small cell lung cancer (NSCLC) remain unclear. We showed that G‐Rh2 had a synergistic antitumor effect with cyclophosphamide (CY) on mice with NSCLC, and improved the immune deficiency caused by CY. Consistently, G‐Rh2 exhibited no inhibitory effect on tumor growth of T cells‐deficient nude mice. Furthermore, G‐Rh2 treatment triggered the oxidative decomposition of fatty acid (FA), suppressed FA synthesis, increased ketone level, and decreased glucocorticoid (CORT) secretion. G‐Rh2 significantly down‐regulated the expression of fatty acid synthase (FASN). Of note, in liver‐specific FASN knockout mice G‐Rh2 failed to show the same immune enhancement effects. Further mechanistic exploration revealed that G‐Rh2 suppressed the expression and nuclear translocation of sterol regulatory element binding protein 1 (SREBP‐1), and disturbed the SREBP‐1–FASN interaction in vitro.

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“…Srebp was required for the increase in both glycolysis and OXPHOS. Moreover, Srebp inhibition prevented this phenotype and decreased NK cell cytotoxicity (Assmann et al, 2017). It remains unclear, however, whether metabolic alterations found in tumors may affect the metabolic activity and the Srebp-mediated NK cell function.…”

Section: Tumors Modulate Local Concentrations Of Nutrients That Are Cmentioning

confidence: 99%

Immunometabolism in cancer at a glance

Singer

Cheng

Kreutz

et al. 2018

Disease Models &Amp; Mechanisms

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The scientific knowledge about tumor metabolism has grown at a fascinating rate in recent decades. We now know that tumors are highly active both in their metabolism of available nutrients and in the secretion of metabolic by-products. However, cancer cells can modulate metabolic pathways and thus adapt to specific nutrients. Unlike tumor cells, immune cells are not subject to a ‘micro-evolution’ that would allow them to adapt to progressing tumors that continuously develop new mechanisms of immune escape. Consequently, immune cells are often irreversibly affected and may allow or even support cancer progression. The mechanisms of how tumors change immune cell function are not sufficiently explored. It is, however, clear that commonly shared features of tumor metabolism, such as local nutrient depletion or production of metabolic ‘waste’ can broadly affect immune cells and contribute to immune evasion. Moreover, immune cells utilize different metabolic programs based on their subtype and function, and these immunometabolic pathways can be modified in the tumor microenvironment. In this review and accompanying poster, we identify and describe the common mechanisms by which tumors metabolically affect the tumor-infiltrating cells of native and adaptive immunity, and discuss how these mechanisms may lead to novel therapeutic opportunities.

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Srebp-controlled glucose metabolism is essential for NK cell functional responses

Cited by 279 publications

References 57 publications

NK cell metabolism

NK cell metabolism

Ginsenoside Rh2 reverses cyclophosphamide-induced immune deficiency by regulating fatty acid metabolism

Immunometabolism in cancer at a glance

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