Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance
Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance
复制标题
线粒体碎片限制了基于 NK 细胞的肿瘤免疫监视
DOI：
10.1038/s41590-019-0511-1
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发表时间：
2019-12-01
影响因子：
30.5
通讯作者：
Wei, Haiming
中科院分区：
文献类型：
--
作者：
Zheng, Xiaohu;Qian, Yeben;Wei, Haiming
自然杀伤（NK）细胞在肿瘤监测中起着至关重要的作用。我们发现，人类肝癌中的肿瘤浸润NK细胞在其细胞质中具有小的碎片化线粒体，而肿瘤外的肝脏NK细胞以及外周NK细胞具有正常的大管状线粒体。这种片段化与降低的细胞毒性和NK细胞损失相关，导致肿瘤逃避NK细胞介导的监视，这预示着肝癌患者的生存率很低。低氧肿瘤微环境驱动NK细胞中雷帕霉素-GTdR动力蛋白相关蛋白1（mTOR-Drp 1）的机械靶点的持续活化，导致过度的线粒体分裂成片段。抑制线粒体断裂改善了NK细胞的线粒体代谢、存活和抗肿瘤能力。这些数据揭示了一种免疫逃逸机制，这种机制可能是有针对性的，并且可以激活基于NK细胞的癌症治疗。
Natural killer (NK) cells have crucial roles in tumor surveillance. We found that tumor-infiltrating NK cells in human liver cancers had small, fragmented mitochondria in their cytoplasm, whereas liver NK cells outside tumors, as well as peripheral NK cells, had normal large, tubular mitochondria. This fragmentation was correlated with reduced cytotoxicity and NK cell loss, resulting in tumor evasion of NK cell-mediated surveillance, which predicted poor survival in patients with liver cancer. The hypoxic tumor microenvironment drove the sustained activation of mechanistic target of rapamycin-GTPase dynamin-related protein 1 (mTOR-Drp1) in NK cells, resulting in excessive mitochondrial fission into fragments. Inhibition of mitochondrial fragmentation improved mitochondrial metabolism, survival and the antitumor capacity of NK cells. These data reveal a mechanism of immune escape that might be targetable and could invigorate NK cell-based cancer treatments.