Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia.
Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia.
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慢性IL-15刺激和损伤mTOR信号和代谢在急性髓系白血病的自然杀伤细胞。
DOI：
10.3389/fimmu.2021.730970
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发表时间：
2021
影响因子：
7.3
通讯作者：
Fauriat C
中科院分区：
文献类型：
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作者：
Bou-Tayeh B;Laletin V;Salem N;Just-Landi S;Fares J;Leblanc R;Balzano M;Kerdiles YM;Bidaut G;Hérault O;Olive D;Aurrand-Lions M;Walzer T;Nunès JA;Fauriat C
自然杀伤(NK)细胞是一种有效的抗白血病免疫效应器。然而，在急性髓系白血病(AML)患者中，它们表现出多种缺陷，导致抗肿瘤潜力降低。我们对这些缺陷的潜在机制的有限理解阻碍了恢复NK细胞潜能的策略的发展。在这里，我们使用了AML的小鼠模型来深入了解这些机制。我们发现白血病进展导致NK细胞成熟缺陷和功能改变。接下来，我们评估了控制其行为的NK细胞细胞因子信号。我们发现白血病小鼠的NK细胞具有组成性的IL-15/mTOR信号和I型干扰素信号。然而，这些细胞在体外对IL-15刺激没有反应，mTOR通路的激活减少就说明了这一点。此外，我们的数据表明，携带AML的小鼠的NK细胞中mTOR介导的代谢反应减少。值得注意的是，在AML的发展过程中，mTOR介导的NK细胞活化的减少部分挽救了NK细胞的代谢和功能缺陷。总之，我们的数据强烈表明，由于慢性细胞因子激活，至少部分是IL-15/mTOR信号，白血病小鼠的NK细胞在代谢和功能上耗尽。急性髓细胞白血病患者NK细胞IL-2/15Rβ表达降低，体外对IL-15刺激的代谢反应减弱，提示急性髓细胞白血病患者可能存在类似的机制。我们的研究指出，细胞因子刺激通路的失调是导致急性髓系白血病NK细胞缺陷的新机制。
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.