Transcriptional Regulation of NK Cell Development by mTOR Complexes

Malarkannan, Subramaniam

doi:10.3389/fcell.2020.566090

Cited by 19 publications

(14 citation statements)

References 150 publications

(228 reference statements)

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“…This resulted in a lack of proliferation and was accompanied by a delayed induction of mTOR phosphorylation. Cytokines such as IL-2, IL-15 and IL-21 are known to relay their signals via mTOR, and mTOR plays an important role in the maturation, activation and metabolism of NK cells [ 18 , 19 ]. A previous study also showed a direct interaction between mTOR and HK1 [ 20 ], which could explain why we observed a delayed upregulation of HK1.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Glucose Uptake Blocks Proliferation but Not Cytotoxic Activity of NK Cells

Picard

Littwitz-Salomon

Waldmann

et al. 2022

Cells

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Tumor cells often have very high energy demands. Inhibition of glucose uptake is therefore a possible approach to limit the proliferation and survival of transformed cells. However, immune cells also require energy to initiate and to maintain anti-tumor immune reactions. Here, we investigate the effect of Glutor, an inhibitor of glucose transporters, on the function of human Natural Killer (NK) cells, which are important for the immunosurveillance of cancer. Glutor treatment effectively inhibits glycolysis in NK cells. However, acute treatment with the inhibitor has no effect on NK cell effector functions. Prolonged inhibition of glucose uptake by Glutor prevents the proliferation of NK cells, increases their pro-inflammatory regulatory function and reduces the stimulation-dependent production of IFN-γ. Interestingly, even after prolonged Glutor treatment NK cell cytotoxicity and serial killing activity were still intact, demonstrating that cytotoxic NK cell effector functions are remarkably robust against metabolic disturbances.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Glucose Uptake Blocks Proliferation but Not Cytotoxic Activity of NK Cells

Picard

Littwitz-Salomon

Waldmann

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

“…NKs are associated with CD122 expression and the loss of CD34 and CD127. Notably, the expression of T-bet and Eomes is required for the further differentiation of functional NK cells [ 70 – 72 ]. In mice, CLP cells produce CILCP, which successively generates NK cells as well as helper-like ILCs.…”

Section: Development Classification and Distribution Of Nk Cellsmentioning

confidence: 99%

“…Since NK cells express many surface markers, unique approaches exist for classifying distinct subsets of NK cells [ 70 , 75 , 76 ]. Based on CD56 expression, they are categorized into two cell subsets, namely CD56 low/dim and CD56 bright .…”

Section: Development Classification and Distribution Of Nk Cellsmentioning

confidence: 99%

Natural killer cells: a promising immunotherapy for cancer

et al. 2022

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As a promising alternative platform for cellular immunotherapy, natural killer cells (NK) have recently gained attention as an important type of innate immune regulatory cell. NK cells can rapidly kill multiple adjacent cancer cells through non-MHC-restrictive effects. Although tumors may develop multiple resistance mechanisms to endogenous NK cell attack, in vitro activation, expansion, and genetic modification of NK cells can greatly enhance their anti-tumor activity and give them the ability to overcome drug resistance. Some of these approaches have been translated into clinical applications, and clinical trials of NK cell infusion in patients with hematological malignancies and solid tumors have thus far yielded many encouraging clinical results. CAR-T cells have exhibited great success in treating hematological malignancies, but their drawbacks include high manufacturing costs and potentially fatal toxicity, such as cytokine release syndrome. To overcome these issues, CAR-NK cells were generated through genetic engineering and demonstrated significant clinical responses and lower adverse effects compared with CAR-T cell therapy. In this review, we summarize recent advances in NK cell immunotherapy, focusing on NK cell biology and function, the types of NK cell therapy, and clinical trials and future perspectives on NK cell therapy.

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“…Metformin and rapamycin, inhibitors of mammalian target of rapamycin signaling, have also been shown to reverse the specific immune dysfunction associated with aging and trigger higher antibody responses and improved cellular immunity to several vaccines including influenza [143][144][145][146][147] . Both rapamycin and metformin are well known to impact transcriptional, functional and epigenetic profiles of innate immunity triggered by the microbiome and/ or metabolites [148][149][150][151][152] . This concept of personalized vaccination has been suggested before (topic reviewed in ref.…”

Section: How To Overcome Poor Vaccine Responses In Immunocompromised ...mentioning

confidence: 99%

Fighting the SARS-CoV-2 pandemic requires a global approach to understanding the heterogeneity of vaccine responses

et al. 2022

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ver the past two decades, the world has experienced a substantial number of disease outbreaks from viral infections including yellow fever, dengue fever, Ebola, Zika, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome and the ongoing novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic 1 . The SARS-CoV-2 pandemic has illuminated how disruptive sustained infectious disease outbreaks can be on society. Given the unpredictability of when the next pandemic will emerge, strengthening our ability to respond rapidly to any infectious disease threat is a global priority.In what may be one of the most impressive accomplishments of modern medicine, multiple effective vaccines were developed against SARS-CoV-2 in less than 12 months after the initial outbreak. As of February 2022 ten coronavirus disease 2019 (COVID-19) vaccines are currently approved for full or emergency use authorization by the World Health Organization (https://covid19.trackvaccines.org/agency/who/). These approved vaccines span four distinct vaccine platforms, providing an additional layer of diversity in potential vaccine responses. The Moderna and Pfizer-BioNTech vaccines both use modified mRNAs to produce antigen upon vaccination 2,3 . Both vaccines use lipid nanoparticle-encapsulated formulations to deliver mRNA that encodes for a prefusion stabilized, full-length SARS-CoV-2 spike (S) protein. The Johnson & Johnson (Ad26 vector) and AstraZeneca AZD1222 (ChAdOx1 vector) vaccines use distinct replication-incompetent adenoviral vectors to deliver antigen (the prefusion stabilized, full-length S protein) 4,5 . The Sinopharm and Sinovac-CoronaVac platforms utilize β-propiolactone-inactivated virus produced in Vero E6 cells and are formulated with the adjuvant alum to promote immunogenicity 6,7 . Protein subunit-based platforms are in advanced stages of development, with one approved for emergency use authorization in Indonesia (Novavax 8 ; clinical trial no. NCT04742738). Approved vaccines have efficacy rates of ~50-95%, with Moderna and Pfizer exhibiting the highest rates of short-term efficacy.

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Transcriptional Regulation of NK Cell Development by mTOR Complexes

Cited by 19 publications

References 150 publications

Inhibition of Glucose Uptake Blocks Proliferation but Not Cytotoxic Activity of NK Cells

Inhibition of Glucose Uptake Blocks Proliferation but Not Cytotoxic Activity of NK Cells

Natural killer cells: a promising immunotherapy for cancer

Fighting the SARS-CoV-2 pandemic requires a global approach to understanding the heterogeneity of vaccine responses

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