PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma.
PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma.
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DOI：
10.18632/oncotarget.12150
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发表时间：
2016-11-08
期刊：
影响因子：
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通讯作者：
Caillat-Zucman S
中科院分区：
文献类型：
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作者：
Beldi-Ferchiou A;Lambert M;Dogniaux S;Vély F;Vivier E;Olive D;Dupuy S;Levasseur F;Zucman D;Lebbé C;Sène D;Hivroz C;Caillat-Zucman S
程序性死亡-1（PD-1）是一种由活化淋巴细胞表达的抑制性受体，参与调节T细胞和B细胞反应。PD-1及其配体被多种癌症利用，以通过PD-1介导的效应T细胞的功能耗竭来促进肿瘤逃逸。在这里，我们报告说，PD-1上调自然杀伤（NK）细胞从卡波西肉瘤（KS）患者。PD-1在活化的成熟CD 56 dimCD 16 pos NK细胞亚群中表达，NK表面受体表达正常。在直接触发NKp 30、NKp 46或CD 16活化受体或用NK细胞靶点短刺激后，来自KS患者的PD-1 pos NK细胞离体低反应。PD-1 pos NK细胞不能去活化和释放IFNγ，但外源性IL-2或IL-15恢复了这一缺陷。在PD-1转导的NKL细胞中证实了PD-1导致NK细胞功能障碍，而不仅仅是功能障碍的NK细胞的标志物。在体外，在与表达活化配体的细胞长时间接触后，在健康对照NK细胞的表面诱导PD-1，即模拟肿瘤细胞持续刺激的条件。因此，PD-1似乎在介导NK细胞耗竭中起关键作用。这种负检查点微调NK活化的存在突出了PD-1通路的操纵可能是一种不仅规避T细胞介导的免疫监视而且规避NK细胞介导的免疫监视的肿瘤逃逸策略的可能性。
Programmed Death-1 (PD-1), an inhibitory receptor expressed by activated lymphocytes, is involved in regulating T- and B-cell responses. PD-1 and its ligands are exploited by a variety of cancers to facilitate tumor escape through PD-1-mediated functional exhaustion of effector T cells. Here, we report that PD-1 is upregulated on Natural Killer (NK) cells from patients with Kaposi sarcoma (KS). PD-1 was expressed in a sub-population of activated, mature CD56dimCD16pos NK cells with otherwise normal expression of NK surface receptors. PD-1pos NK cells from KS patients were hyporesponsive ex vivo following direct triggering of NKp30, NKp46 or CD16 activating receptors, or short stimulation with NK cell targets. PD-1pos NK cells failed to degranulate and release IFNγ, but exogenous IL-2 or IL-15 restored this defect. That PD-1 contributed to NK cell functional impairment and was not simply a marker of dysfunctional NK cells was confirmed in PD-1-transduced NKL cells. In vitro, PD-1 was induced at the surface of healthy control NK cells upon prolonged contact with cells expressing activating ligands, i.e. a condition mimicking persistent stimulation by tumor cells. Thus, PD-1 appears to plays a critical role in mediating NK cell exhaustion. The existence of this negative checkpoint fine-tuning NK activation highlights the possibility that manipulation of the PD-1 pathway may be a strategy for circumventing tumor escape not only from the T cell-, but also the NK-cell mediated immune surveillance.