Woo Seng-Ryong, Fuertes Mercedes B, Corrales Leticia, Spranger Stefani, Furdyna Michael J, Leung Michael Y K, Duggan Ryan, Wang Ying, Barber Glen N, Fitzgerald Katherine A, Alegre Maria-Luisa, Gajewski Thomas F
Department of Pathology, The University of Chicago, 929 E57th Street GCIS W423H, Chicago, IL 60637, USA.
Flow Cytometry Core Facility, The University of Chicago, 924 E57th Street r022, Chicago, IL 60637, USA.
Immunity. 2014 Nov 20;41(5):830-42. doi: 10.1016/j.immuni.2014.10.017. Epub 2014 Nov 5.
Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-? production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-? production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy.
针对肿瘤的自发性T细胞反应频繁发生，且对患者具有预后价值。尽管I型干扰素（IFN）参与了这一过程，但导致适应性T细胞反应的免疫原性肿瘤的天然免疫感知机制仍不明确。我们发现，在缺乏干扰素基因刺激物复合物（STING）的小鼠中，针对肿瘤的自发性CD8(+) T细胞启动存在缺陷，但其他天然信号通路无此缺陷，这表明细胞溶质DNA传感通路参与其中。在体外，肿瘤细胞衍生的DNA通过环磷酸鸟苷-腺苷酸合酶（cGAS）、STING和干扰素调节因子3（IRF3）触发IFN-γ产生和树突状细胞活化。在体内肿瘤微环境中，在宿主抗原呈递细胞内检测到肿瘤细胞DNA，这与STING通路激活和IFN-γ产生相关。我们的结果表明，癌症天然免疫感知的主要机制是通过宿主STING通路发生的，这对癌症免疫治疗具有重要意义。
