TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer.
TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer.
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TGFβ驱动人转移性乳腺癌中的NK细胞代谢功能障碍。
DOI：
10.1136/jitc-2020-002044
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发表时间：
2021-03
影响因子：
10.9
通讯作者：
Gardiner CM
中科院分区：
文献类型：
--
作者：
Slattery K;Woods E;Zaiatz-Bittencourt V;Marks S;Chew S;Conroy M;Goggin C;MacEochagain C;Kennedy J;Lucas S;Finlay DK;Gardiner CM
自然杀伤(NK)细胞提供对癌症的重要免疫保护，是特殊免疫疗法的关键要求。越来越多的证据表明，自然杀伤细胞在癌症期间会变得功能失调。克服NK细胞衰竭将是重要的一步，使它们能够在一系列NK细胞疗法中发挥最佳功能，包括那些依赖自体循环NK细胞的疗法。我们之前已经证明，NK细胞在细胞因子激活后经历正常的代谢重编程，这是最佳功能所必需的。这项工作的目的是调查转移性乳腺癌患者循环中NK细胞的细胞代谢是否失调，如果是，则深入了解其潜在机制。这些发现将为如何充分释放NK细胞的活性以最大限度地发挥免疫治疗效果提供重要的见解。转移性乳腺癌患者和健康对照的NK细胞的单细胞分析、代谢通量和共聚焦分析除了干扰素-γ的产生和细胞毒性降低外，患者的外周血NK细胞还存在明显的代谢缺陷，包括糖酵解和氧化磷酸化降低。线粒体也有明显的形态改变，线粒体碎裂增加。转化生长因子-β(转化生长因子-β)被认为是这一表型的关键驱动因素，因为它阻断了它的活性，逆转了许多代谢和功能读数。部分患者NK细胞表达与新的转化生长因子β加工途径有关的糖蛋白A重复序列(GARP)和潜伏期相关肽(LAP)。阻断GARP-转化生长因子β轴概括了转化生长因子β中和的作用，首次强调GARP是一种新的NK细胞免疫治疗靶点。转化生长因子β在转移性乳腺癌患者循环NK细胞代谢紊乱中起重要作用。阻断转化生长因子β和/或GARP可以恢复NK细胞的代谢和功能，是改进NK细胞免疫治疗的重要靶点。
Natural killer (NK) cells provide important immune protection from cancer and are a key requirement for particular immunotherapies. There is accumulating evidence that NK cells become dysfunctional during cancer. Overcoming NK cell exhaustion would be an important step to allow them to function optimally in a range of NK cell therapies, including those that depend on autologos circulating NK cells. We have previously demonstrated that NK cells undergo a normal metabolic reprogramming in response to cytokine activation and that this is required for optimal function. The objective of this work was to investigate if cellular metabolism of circulating NK cells is dysregulated in patients with metastatic breast cancer and if so, to gain insights into potential mechanisms underpinning this. Such discoveries would provide important insights into how to unleash the full activity of NK cells for maximum immunotherapy output. Single-cell analysis, metabolic flux and confocal analysis of NK cells from patients with metastatic breast cancer and healthy controls In addition to reduced interferon-γ production and cytotoxicity, peripheral blood NK cells from patients had clear metabolic deficits including reduced glycolysis and oxidative phosphorylation. There were also distinct morphologically alterations in the mitochondria with increased mitochondrial fragmentation observed. Transforminggrowth factor-β (TGFβ) was identified as a key driver of this phenotype as blocking its activity reversed many metabolic and functional readouts. Expression of glycoprotein-A repetitions predominant (GARP) and latency associated peptide (LAP), which are involved with a novel TGFβ processing pathway, was increased on NK cells from some patients. Blocking the GARP–TGFβ axis recapitulated the effects of TGFβ neutralization, highlighting GARP as a novel NK cell immunotherapy target for the first time. TGFβ contributes to metabolic dysfunction of circulating NK cells in patients with metastatic breast cancer. Blocking TGFβ and/or GARP can restore NK cell metabolism and function and is an important target for improving NK cell-based immunotherapies.
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影响因子：
11.2
作者：
Metelli A;Wu BX;Fugle CW;Rachidi S;Sun S;Zhang Y;Wu J;Tomlinson S;Howe PH;Yang Y;Garrett-Mayer E;Liu B;Li Z
通讯作者：
Li Z
影响因子：
15.9
作者：
Mamessier, Emilie;Sylvain, Aude;Olive, Daniel
通讯作者：
Olive, Daniel
影响因子：
17.1
作者：
Cuende, Julia;Lienart, Stephanie;Lucas, Sophie
通讯作者：
Lucas, Sophie
影响因子：
14.2
作者：
Schafer, Jolie R.;Salzillo, Travis C.;Lee, Dean A.
通讯作者：
Lee, Dean A.
影响因子：
8
作者：
Mah, Annelise Y.;Rashidi, Armin;Cooper, Megan A.
通讯作者：
Cooper, Megan A.