Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia

Natural Killer (NK) cells are potent anti-leukemic immune effectors. However, they display multiple defects in acute myeloid leukemia (AML) patients leading to reduced anti-tumor potential. Our limited understanding of the mechanisms underlying these defects hampers the development of strategies to...

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Published inFrontiers in immunology Vol. 12; p. 730970
Main Authors Bou-Tayeh, Berna, Laletin, Vladimir, Salem, Nassim, Just-Landi, Sylvaine, Fares, Joanna, Leblanc, Raphael, Balzano, Marielle, Kerdiles, Yann M, Bidaut, Ghislain, Hérault, Olivier, Olive, Daniel, Aurrand-Lions, Michel, Walzer, Thierry, Nunès, Jacques A, Fauriat, Cyril
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Published Switzerland Frontiers 17.12.2021
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Abstract Natural Killer (NK) cells are potent anti-leukemic immune effectors. However, they display multiple defects in acute myeloid leukemia (AML) patients leading to reduced anti-tumor potential. Our limited understanding of the mechanisms underlying these defects hampers the development of strategies to restore NK cell potential. Here, we have used a mouse model of AML to gain insight into these mechanisms. We found that leukemia progression resulted in NK cell maturation defects and functional alterations. Next, we assessed NK cell cytokine signaling governing their behavior. We showed that NK cells from leukemic mice exhibit constitutive IL-15/mTOR signaling and type I IFN signaling. However, these cells failed to respond to IL-15 stimulation as illustrated by reduced activation of the mTOR pathway. Moreover, our data suggest that mTOR-mediated metabolic responses were reduced in NK cells from AML-bearing mice. Noteworthy, the reduction of mTOR-mediated activation of NK cells during AML development partially rescued NK cell metabolic and functional defects. Altogether, our data strongly suggest that NK cells from leukemic mice are metabolically and functionally exhausted as a result of a chronic cytokine activation, at least partially IL-15/mTOR signaling. NK cells from AML patients also displayed reduced IL-2/15Rβ expression and showed cues of reduced metabolic response to IL-15 stimulation , suggesting that a similar mechanism might occur in AML patients. Our study pinpoints the dysregulation of cytokine stimulation pathways as a new mechanism leading to NK cell defects in AML.
AbstractList Natural Killer (NK) cells are potent anti-leukemic immune effectors. However, they display multiple defects in acute myeloid leukemia (AML) patients leading to reduced anti-tumor potential. Our limited understanding of the mechanisms underlying these defects hampers the development of strategies to restore NK cell potential. Here, we have used a mouse model of AML to gain insight into these mechanisms. We found that leukemia progression resulted in NK cell maturation defects and functional alterations. Next, we assessed NK cell cytokine signaling governing their behavior. We showed that NK cells from leukemic mice exhibit constitutive IL-15/mTOR signaling and type I IFN signaling. However, these cells failed to respond to IL-15 stimulation in vitro as illustrated by reduced activation of the mTOR pathway. Moreover, our data suggest that mTOR-mediated metabolic responses were reduced in NK cells from AML-bearing mice. Noteworthy, the reduction of mTOR-mediated activation of NK cells during AML development partially rescued NK cell metabolic and functional defects. Altogether, our data strongly suggest that NK cells from leukemic mice are metabolically and functionally exhausted as a result of a chronic cytokine activation, at least partially IL-15/mTOR signaling. NK cells from AML patients also displayed reduced IL-2/15Rβ expression and showed cues of reduced metabolic response to IL-15 stimulation in vitro, suggesting that a similar mechanism might occur in AML patients. Our study pinpoints the dysregulation of cytokine stimulation pathways as a new mechanism leading to NK cell defects in AML.
Natural Killer (NK) cells are potent anti-leukemic immune effectors. However, they display multiple defects in acute myeloid leukemia (AML) patients leading to reduced anti-tumor potential. Our limited understanding of the mechanisms underlying these defects hampers the development of strategies to restore NK cell potential. Here, we have used a mouse model of AML to gain insight into these mechanisms. We found that leukemia progression resulted in NK cell maturation defects and functional alterations. Next, we assessed NK cell cytokine signaling governing their behavior. We showed that NK cells from leukemic mice exhibit constitutive IL-15/mTOR signaling and type I IFN signaling. However, these cells failed to respond to IL-15 stimulation in vitro as illustrated by reduced activation of the mTOR pathway. Moreover, our data suggest that mTOR-mediated metabolic responses were reduced in NK cells from AML-bearing mice. Noteworthy, the reduction of mTOR-mediated activation of NK cells during AML development partially rescued NK cell metabolic and functional defects. Altogether, our data strongly suggest that NK cells from leukemic mice are metabolically and functionally exhausted as a result of a chronic cytokine activation, at least partially IL-15/mTOR signaling. NK cells from AML patients also displayed reduced IL-2/15Rβ expression and showed cues of reduced metabolic response to IL-15 stimulation in vitro , suggesting that a similar mechanism might occur in AML patients. Our study pinpoints the dysregulation of cytokine stimulation pathways as a new mechanism leading to NK cell defects in AML.
Natural Killer (NK) cells are potent anti-leukemic immune effectors. However, they display multiple defects in acute myeloid leukemia (AML) patients leading to reduced anti-tumor potential. Our limited understanding of the mechanisms underlying these defects hampers the development of strategies to restore NK cell potential. Here, we have used a mouse model of AML to gain insight into these mechanisms. We found that leukemia progression resulted in NK cell maturation defects and functional alterations. Next, we assessed NK cell cytokine signaling governing their behavior. We showed that NK cells from leukemic mice exhibit constitutive IL-15/mTOR signaling and type I IFN signaling. However, these cells failed to respond to IL-15 stimulation as illustrated by reduced activation of the mTOR pathway. Moreover, our data suggest that mTOR-mediated metabolic responses were reduced in NK cells from AML-bearing mice. Noteworthy, the reduction of mTOR-mediated activation of NK cells during AML development partially rescued NK cell metabolic and functional defects. Altogether, our data strongly suggest that NK cells from leukemic mice are metabolically and functionally exhausted as a result of a chronic cytokine activation, at least partially IL-15/mTOR signaling. NK cells from AML patients also displayed reduced IL-2/15Rβ expression and showed cues of reduced metabolic response to IL-15 stimulation , suggesting that a similar mechanism might occur in AML patients. Our study pinpoints the dysregulation of cytokine stimulation pathways as a new mechanism leading to NK cell defects in AML.
Author Fares, Joanna
Bou-Tayeh, Berna
Aurrand-Lions, Michel
Leblanc, Raphael
Bidaut, Ghislain
Walzer, Thierry
Balzano, Marielle
Just-Landi, Sylvaine
Salem, Nassim
Laletin, Vladimir
Kerdiles, Yann M
Olive, Daniel
Fauriat, Cyril
Nunès, Jacques A
Hérault, Olivier
AuthorAffiliation 5 Centre National de la Recherche Scientifique (CNRS) UMR 7292, LNOx Team, François Rabelais University , Tours , France
4 Cibi Technological Platform, Cancer Research Center of Marseille (CRCM) , Marseille , France
2 IBiSA Immunomonitoring Platform, Institut Paoli-Calmettes, Cancer Research Center of Marseille (CRCM) , Marseille , France
3 Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille-Luminy (CIML) , Marseille , France
6 Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, CNRS UMR5308 , Lyon , France
1 Aix-Marseille Université UM105, Centre National de la Recherche Scientifique (CNRS) UMR7258, Inserm UMR1068, Institut Paoli-Calmettes, Cancer Research Center of Marseille (CRCM) , Marseille , France
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– name: 3 Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille-Luminy (CIML) , Marseille , France
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  givenname: Jacques A
  surname: Nunès
  fullname: Nunès, Jacques A
  organization: Aix-Marseille Université UM105, Centre National de la Recherche Scientifique (CNRS) UMR7258, Inserm UMR1068, Institut Paoli-Calmettes, Cancer Research Center of Marseille (CRCM), Marseille, France
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ContentType Journal Article
Copyright Copyright © 2021 Bou-Tayeh, Laletin, Salem, Just-Landi, Fares, Leblanc, Balzano, Kerdiles, Bidaut, Hérault, Olive, Aurrand-Lions, Walzer, Nunès and Fauriat.
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Copyright © 2021 Bou-Tayeh, Laletin, Salem, Just-Landi, Fares, Leblanc, Balzano, Kerdiles, Bidaut, Hérault, Olive, Aurrand-Lions, Walzer, Nunès and Fauriat 2021 Bou-Tayeh, Laletin, Salem, Just-Landi, Fares, Leblanc, Balzano, Kerdiles, Bidaut, Hérault, Olive, Aurrand-Lions, Walzer, Nunès and Fauriat
Copyright_xml – notice: Copyright © 2021 Bou-Tayeh, Laletin, Salem, Just-Landi, Fares, Leblanc, Balzano, Kerdiles, Bidaut, Hérault, Olive, Aurrand-Lions, Walzer, Nunès and Fauriat.
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Keywords exhaustion
natural killer cells
IL-15/mTOR signaling
metabolism
acute myeloid leukemia
chronic stimulation
Language English
License Copyright © 2021 Bou-Tayeh, Laletin, Salem, Just-Landi, Fares, Leblanc, Balzano, Kerdiles, Bidaut, Hérault, Olive, Aurrand-Lions, Walzer, Nunès and Fauriat.
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PMCID: PMC8718679
Edited by: Salvatore Valitutti, Institut National de la Santé et de la Recherche Médicale (INSERM), France
Reviewed by: Alvaro Teijeira, University of Navarra, Spain; Laura Patrussi, University of Siena, Italy
Present address: Joanna Fares, Innate Pharma S.A., Marseille, France; Marielle Balzano, BioCytex, Marseille, France
This article was submitted to T Cell Biology, a section of the journal Frontiers in Immunology
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Snippet Natural Killer (NK) cells are potent anti-leukemic immune effectors. However, they display multiple defects in acute myeloid leukemia (AML) patients leading to...
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StartPage 730970
SubjectTerms acute myeloid leukemia
Animals
Case-Control Studies
Cells, Cultured
chronic stimulation
Disease Models, Animal
exhaustion
Female
Humans
IL-15/mTOR signaling
Immunology
Interleukin-15 - metabolism
Interleukin-15 - pharmacology
Killer Cells, Natural - immunology
Leukemia, Myeloid, Acute - blood
Leukemia, Myeloid, Acute - immunology
Life Sciences
Male
metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
natural killer cells
Signal Transduction - drug effects
Signal Transduction - genetics
TOR Serine-Threonine Kinases - metabolism
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Title Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia
URI https://www.ncbi.nlm.nih.gov/pubmed/34975835
https://search.proquest.com/docview/2616281882
https://amu.hal.science/hal-03566016
https://pubmed.ncbi.nlm.nih.gov/PMC8718679
https://doaj.org/article/4769fe68b51142dbbb9fe377ecb4b15a
Volume 12
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