STING信号通路促进自然杀伤细胞的抗肿瘤免疫和维持TCF-1+自然杀伤细胞的库存。
STING signaling promotes NK cell antitumor immunity and maintains a reservoir of TCF-1+ NK cells.
发表日期：2023 Sep 13
作者：
Lu Lu, Chao Yang, Xingyue Zhou, Lingling Wu, Xiaochuan Hong, Wenwen Li, Xinran Wang, Yuanqin Yang, Dongqing Cao, Ao Zhang, Wen Di, Liufu Deng
来源：
Cell Reports
摘要：
自然杀伤性（NK）细胞是一类细胞毒性的先天淋巴细胞，可消灭肿瘤细胞。通过NK细胞诱导持久的抗肿瘤免疫反应是癌症免疫治疗的主要优先事项。虽然细胞质DNA感知在启动抗肿瘤免疫中起着重要作用，但NK细胞内在的STING信号传导的作用尚不清楚。在这里，我们发现NK细胞内在的STING促进抗肿瘤反应并维持TCF-1阳性（TCF-1+）NK细胞库。相反，肿瘤细胞内在的cGAS和线粒体DNA（mtDNA）对NK细胞的抗肿瘤活性至关重要，表明肿瘤mtDNA的识别部分触发了NK细胞内在的STING激活。此外，添加cGAMP可以在体外支持NK细胞的STING激活和Ⅰ型干扰素产生，从而促进NK细胞的激活。在人体中，STING激动剂促进了TCF-1阳性（TCF-1+）NK细胞的扩展。本研究揭示了STING信号如何驱动NK细胞的抗肿瘤免疫以及发展基于NK细胞的癌症免疫治疗的机制。2023 The Authors. Published by Elsevier Inc. All rights reserved.
Natural killer (NK) cells are cytotoxic innate lymphocytes that eradicate tumor cells. Inducing durable antitumor immune responses by NK cells represents a major priority of cancer immunotherapy. While cytosolic DNA sensing plays an essential role in initiating antitumor immunity, the role of NK cell-intrinsic STING signaling remains unclear. Here, we find that NK cell-intrinsic STING promotes antitumor responses and maintains a reservoir of TCF-1+ NK cells. In contrast, tumor cell-intrinsic cGAS and mtDNA are required for NK cell antitumor activity, indicating that tumor mtDNA recognition by cGAS partially triggers NK cell-intrinsic STING activation. Moreover, addition of cGAMP enables STING activation and type I interferon production in NK cells, thereby supporting the activation of NK cells in vitro. In humans, STING agonism promotes the expansion of TCF-1+ NK cells. This study provides insight into understanding how STING signaling drives NK cell antitumor immunity and the development of NK cell-based cancer immunotherapy.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.