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

Autor:	Bou-Tayeh B; 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., Laletin V; 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., Salem N; 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., Just-Landi S; 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.; IBiSA Immunomonitoring Platform, Institut Paoli-Calmettes, Cancer Research Center of Marseille (CRCM), Marseille, France., Fares J; 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., Leblanc R; 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., Balzano M; 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., Kerdiles YM; 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., Bidaut G; 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.; Cibi Technological Platform, Cancer Research Center of Marseille (CRCM), Marseille, France., Hérault O; Centre National de la Recherche Scientifique (CNRS) UMR 7292, LNOx Team, François Rabelais University, Tours, France., Olive D; 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.; IBiSA Immunomonitoring Platform, Institut Paoli-Calmettes, Cancer Research Center of Marseille (CRCM), Marseille, France., Aurrand-Lions M; 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., Walzer T; Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, CNRS UMR5308, Lyon, France., Nunès JA; 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., Fauriat C; 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.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Dec 17; Vol. 12, pp. 730970. Date of Electronic Publication: 2021 Dec 17 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.730970
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Bou-Tayeh, Laletin, Salem, Just-Landi, Fares, Leblanc, Balzano, Kerdiles, Bidaut, Hérault, Olive, Aurrand-Lions, Walzer, Nunès and Fauriat.)
Databáze:	MEDLINE
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