Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control

Mah, Annelise Y.; Rashidi, Armin; Keppel, Molly P.; Saucier, Nermina; Moore, Emily K.; Alinger, Joshua B.; Tripathy, Sandeep K.; Agarwal, Sandeep K.; Jeng, Emily K.; Wong, Hing C.; Miller, Jeffrey S.; Fehniger, Todd A.; Mace, Emily M.; French, Anthony R.; Cooper, Megan A.

doi:10.1172/jci.insight.95128

Cited by 108 publications

(122 citation statements)

References 77 publications

(84 reference statements)

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“…Based on the principles outlined in the Reverse Warburg Effect hypothesis, glycolysis and lactate can be conducive to the growth of tumor cells . It has been previously established that the antitumor activities of NK cells are impaired by hypoxia, acidosis, and glucose metabolic abnormalities . Therefore, repairing the activity of NK cells based on metabolic interventions is considered a reasonable means by which to identify an effective and feasible antitumor intervention.…”

Section: Discussionmentioning

confidence: 99%

“…[37][38][39] It has been previously established that the antitumor activities of NK cells are impaired by hypoxia, acidosis, and glucose metabolic abnormalities. 40,41 Therefore, repairing the activity of NK cells based on metabolic interventions is considered a reasonable means by which to identify an effective and feasible antitumor intervention. The activity of NK cells has been previously documented to decrease sharply with an elevated concentration of lactate.…”

Section: Discussionmentioning

confidence: 99%

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Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma

Long

Gao

et al. 2018

Cancer Medicine

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Monocarboxylate transporter‐4 (MCT4), a monocarboxylic acid transporter, demonstrates significantly increased expression in the majority of malignancies. We performed an experiment using BALB/C mice, and our results showed that ShMCT4 transfection or the pharmaceutic inhibition of MCT4 with 7acc1 strengthens the activity of NK cells. The results of a calcein assay revealed that the cytotoxicity of NK cells was strengthened via inhibition of MCT4. In addition, ELISA testing showed that the content of perforin and CD107a was increased, and PCR amplification and immunoblotting revealed that the expression of NKG2D and H60 was upregulated after the inhibition of MCT4. Further, we observed an elevated pH value, decreased extracellular lactate flow, and attenuated tumor growth. Therefore, we concluded that the inhibition of MCT4 enhanced the cytotoxicity of NK cells by blocking lactate flux and reversing the acidified tumor microenvironment. In addition to these findings, we also discovered that MCT4 depletion may have a pronounced impact on autophagy, which was surmised by observing that the inhibition of autophagy (3MA) pulled the enhanced cytotoxicity of NK cells downwards. Together, these data suggest that the key effect of MCT4 depletion on NK cells probably utilizes inductive autophagy as a compensatory metabolic mechanism to minimize the acidic extracellular microenvironment associated with lactate export in tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma

Long

Gao

et al. 2018

Cancer Medicine

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“…In mice, Mah et al reported that global inhibition of metabolism, using either 2-deoxyglucose (2DG) to block glucose metabolism or rapamycin to block mammalian target of rapamycin 1 (mTORC1), resulted in an increased susceptibility to MCMV mortality that was NK cell dependent. 38 dependent interactions were only partially inhibited. 25 Combined, these studies suggest that mTORC1 and potentially metabolism are important in the early infection but mTORC1 may become less important for NK cell effector responses later on during MCMV infection.…”

Section: The Specific Case Of CMVmentioning

confidence: 93%

“…In mice, Mah et al reported that global inhibition of metabolism, using either 2‐deoxyglucose (2DG) to block glucose metabolism or rapamycin to block mammalian target of rapamycin 1 (mTORC1), resulted in an increased susceptibility to MCMV mortality that was NK cell dependent . Both 2DG and rapamycin inhibited NK cell killing in vitro and in vivo with reduced clearance of adoptively transferred target cells during MCMV infection.…”

Section: What About Nk Cell Metabolism?mentioning

confidence: 99%

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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“…Glycolysis inhibition by 2DG also impaired clearance of NK-specific targets in vivo concomitant to higher viremia and susceptibility to CMV infection 252. However, IL-15 agonist treatment rescued this defect and cleared viremia in a CMV-infected hematopoietic cell transplant patient 252. These authors concluded NK cell-mediated control of viral infection requires glucose metabolism and IL-15 treatment in vivo can reduce this requirement.…”

mentioning

confidence: 99%

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

Bahadoran

Bezavada

Smallwood

2020

Immunological Reviews

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The metabolic impact of influenza A virus (IAV) infections on immune cells remains largely uncharacterized. However, much is known about the metabolism of IAV infection and immunometabolism. Thus, we will consider four main factors: the metabolic requirements of influenza virus, metabolic reprogramming of immune cells that are mobilized to fight IAV infection, the impact of systemic or local metabolism on the infection and immune response, and vice versa. We will also address the interplay of metabolism and cytokines with a focus on those relevant to IAV infections. Finally, we will limit information on immunometabolism to key cell types critical to fighting IAV infection. We will relate this information to the unique metabolic demands on immune cells and discuss how their translocation through nutrient diverse and changing environments may affect their functions in IAV infection. | ME TABOLIS M AND THE LUNG MICROENVIRONMENT | Steady-state metabolismUnder aerobic conditions, cells sustain themselves catabolically using glycolytic carbons to fuel the tricarboxylic acid (TCA) cycle. AbstractRecent studies support the notion that glycolysis and oxidative phosphorylation are rheostats in immune cells whose bioenergetics have functional outputs in terms of their biology. Specific intrinsic and extrinsic molecular factors function as molecular potentiometers to adjust and control glycolytic to respiratory power output. In many cases, these potentiometers are used by influenza viruses and immune cells to support pathogenesis and the host immune response, respectively. Influenza virus infects the respiratory tract, providing a specific environmental niche, while immune cells encounter variable nutrient concentrations as they migrate in response to infection. Immune cell subsets have distinct metabolic programs that adjust to meet energetic and biosynthetic requirements to support effector functions, differentiation, and longevity in their ever-changing microenvironments. This review details how influenza coopts the host cell for metabolic reprogramming and describes the overlap of these regulatory controls in immune cells whose function and fate are dictated by metabolism. These details are contextualized with emerging evidence of the consequences of influenzainduced changes in metabolic homeostasis on disease progression. K E Y W O R D Shost pathogen, immune response, Immunometabolism, Influenza, metabolism, viral infection, virus | 141 BAHADORAN et Al.

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Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control

Cited by 108 publications

References 77 publications

Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma

Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma

NK cell metabolism

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

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