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

Berna Bou-Tayeh (1, 2) , Vladimir Laletin (1, 2) , Nassim Salem (1, 2) , Sylvaine Just-Landi (1, 2) , Joanna Fares (1, 2) , Raphael Leblanc (1, 2) , Marielle Balzano (1, 2) , Yann Kerdiles (3) , Ghislain Bidaut (1, 2) , Olivier Hérault (4) , Daniel Olive (1, 2) , Michel Aurrand-Lions (1, 2) , Thierry Walzer (5) , Jacques Nunès (1, 2) , Cyril Fauriat (1, 2)

1 CRCM - Centre de Recherche en Cancérologie de Marseille
2 IPC - Institut Paoli-Calmettes
3 CIML - Centre d'Immunologie de Marseille - Luminy
4 GICC EA 7501 - Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...]
5 CIRI - Centre International de Recherche en Infectiologie

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.

Mots clés: IL-15/mTOR signaling; acute myeloid leukemia; chronic stimulation; exhaustion; metabolism; natural killer cells

Domaines: Sciences du Vivant [q-bio]

Berna Bou-Tayeh, Vladimir Laletin, Nassim Salem, Sylvaine Just-Landi, Joanna Fares, et al.. Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia. Frontiers in Immunology, 2021, 12, ⟨10.3389/fimmu.2021.730970⟩. ⟨hal-03566016⟩