Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor Cells to Activate the NK Cell Response.
Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor Cells to Activate the NK Cell Response.
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肿瘤来源的CGAMP触发非肿瘤细胞中的刺激介导的干扰素反应激活NK细胞反应。
DOI：
10.1016/j.immuni.2018.09.016
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发表时间：
2018-10-16
期刊：
影响因子：
32.4
通讯作者：
Raulet DH
中科院分区：
文献类型：
--
作者：
Marcus A;Mao AJ;Lensink-Vasan M;Wang L;Vance RE;Raulet DH
通过酶cGAS检测胞质DNA触发cGAMP的产生，cGAMP是结合并激活衔接蛋白STING的第二信使，其导致干扰素（IFN）产生。在这里，我们发现，在体内，自然杀伤（NK）细胞杀死肿瘤细胞，而不是正常细胞，依赖于STING在非肿瘤细胞中的表达。在STING和cGAS缺陷小鼠中使用可移植肿瘤模型的实验揭示，肿瘤细胞的cGAS表达对于NK细胞的肿瘤排斥至关重要。相比之下，宿主细胞的cGAS表达被抑制，表明肿瘤来源的cGAMP被转移到非肿瘤细胞，在那里它激活STING。cGAMP给药触发了骨髓细胞和B细胞中的STING活化和干扰素-β产生，但不触发NK细胞。我们的研究结果表明，NK细胞的抗肿瘤反应严重依赖于胞质DNA传感途径，类似于其在防御病原体中的作用，并确定肿瘤来源的cGAMP作为肿瘤免疫原性的主要决定因素，对癌症免疫治疗有意义。Marcus等人发现，肿瘤细胞产生的cGAMP触发肿瘤微环境内免疫细胞中STING途径的激活，导致这些细胞产生干扰素，进而激活NK细胞抗肿瘤免疫。
Detection of cytosolic DNA by the enzyme cGAS triggers the production of cGAMP, a second messenger that binds and activates the adaptor protein STING, which leads to interferon (IFN) production. Here we found that in vivo, natural killer (NK) cell killing of tumor cells, but not normal cells, depended on STING expression in non-tumor cells. Experiments using transplantable tumor models in STING and cGAS-deficient mice revealed that cGAS expression by tumor cells was critical for tumor rejection by NK cells. In contrast, cGAS expression by host cells was dispensable, suggesting that tumor-derived cGAMP is transferred to non-tumor cells where it activates STING. cGAMP administration triggered STING activation and interferon-β production in myeloid cells and B cells but not NK cells. Our results revealed that the anti-tumor response of NK cells critically depended on the cytosolic DNA sensing pathway similarly to its role in defense against pathogens, and identified tumor-derived cGAMP as a major determinant of tumor immunogenicity with implications for cancer immunotherapy. Marcus et al. find that cGAMP produced by tumor cells triggers the activation of the STING pathway in immune cells within the tumor microenvironment, leading to interferon production by these cells, which in turn activates NK cell anti-tumor immunity.
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DOI：
10.1073/pnas.1112064108
发表时间：
2011-11-08
影响因子：
11.1
作者：
Narni-Mancinelli, Emilie;Chaix, Julie;Vivier, Eric
通讯作者：
Vivier, Eric
DOI：
10.1084/jem.191.1.129
发表时间：
2000-01-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Glas R;Franksson L;Une C;Eloranta ML;Ohlén C;Orn A;Kärre K
通讯作者：
Kärre K
影响因子：
5.4
作者：
KIESSLING, R;KLEIN, E;WIGZELL, H
通讯作者：
WIGZELL, H
影响因子：
21.3
作者：
Glück S;Guey B;Gulen MF;Wolter K;Kang TW;Schmacke NA;Bridgeman A;Rehwinkel J;Zender L;Ablasser A
通讯作者：
Ablasser A
影响因子：
56.9
作者：
Gentili, Matteo;Kowal, Joanna;Manel, Nicolas
通讯作者：
Manel, Nicolas