Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway
Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway
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DOI：
10.1172/jci.insight.127729
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发表时间：
2019-07-25
期刊：
影响因子：
8
通讯作者：
Negrin, Robert S.
中科院分区：
文献类型：
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作者：
Alvarez, Maite;Simonetta, Federico;Negrin, Robert S.
NK细胞持续增殖导致的NK细胞衰竭(NCE)导致NK细胞功能受损，细胞因子的产生和裂解活性丧失。在小鼠慢性NK细胞刺激模型中，我们发现了NCE的表型特征，其特征是终末分化标记KLRG1上调，eomesodermin和激活受体NKG2D下调。与对照组相比，慢性刺激缺乏NKG2D的小鼠产生了最小的NCE，因此NKG2D是NCE的关键介质。在高表达NKG2D配体(NKG2DL)的肿瘤细胞中，由于DNA损伤修复通路的激活，NKG2D对NK细胞的内化和下调已被观察到。有趣的是，我们的研究发现，在NK细胞激活的过程中，与诱导DNA损伤相关的NKG2DL基因MULT1增加。在激活过程中用ATM DNA损伤修复途径抑制剂KU55933(KU)处理，通过维持NKG2D的表达和保留细胞功能，提高激活标记和参与细胞生存的基因的表达，从而降低NCE。重要的是，在KU存在下体外扩增的NK细胞在NKG2D依赖和非依赖小鼠模型中都显示出更高的抗肿瘤效果。总而言之，这些数据表明，NCE是由DNA损伤引起的，至少部分受NKG2D调控。此外，预防NCE是改进以NK细胞为基础的免疫治疗的一个有前途的策略。
NK cell exhaustion (NCE) due to sustained proliferation results in impaired NK cell function with loss of cytokine production and lytic activity. Using murine models of chronic NK cell stimulation, we have identified a phenotypic signature of NCE, characterized by upregulation of the terminal differentiation marker KLRG1 and by downregulation of eomesodermin and the activating receptor NKG2D. Chronic stimulation of mice lacking NKG2D resulted in minimal NCE compared with control mice, thus identifying NKG2D as a crucial mediator of NCE. NKG2D internalization and downregulation on NK cells have been previously observed in the presence of tumor cells with high expression of NKG2D ligands (NKG2DL) due to the activation of the DNA damage repair pathways. Interestingly, our study revealed that during NK cell activation, there is an increase of MULT1, an NKG2DL, that correlates with an induction of DNA damage. Treatment with the ATM DNA damage repair pathway inhibitor KU55933 (KU) during activation reduced NCE by improving expression of activation markers and genes involved in cell survival, through sustaining NKG2D expression and preserving cell functionality. Importantly, NK cells expanded ex vivo in the presence of KU displayed increased antitumor efficacy in both NKG2D-dependent and -independent mouse models. Collectively, these data demonstrate that NCE is caused by DNA damage and is regulated, at least in part, by NKG2D. Further, the prevention of NCE is a promising strategy to improve NK cell-based immunotherapy.