Ovarian Cancer Cells Commonly Exhibit Defective STING Signaling Which Affects Sensitivity to Viral Oncolysis
Ovarian Cancer Cells Commonly Exhibit Defective STING Signaling Which Affects Sensitivity to Viral Oncolysis
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DOI：
10.1158/1541-7786.mcr-18-0504
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发表时间：
2019-04-01
影响因子：
5.2
通讯作者：
Barber, Glen N.
中科院分区：
文献类型：
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作者：
de Queiroz, Nina Mari Gual Pimenta;Xia, Tianli;Barber, Glen N.
卵巢癌是女性第六大常见癌症，也是最致命的妇科恶性肿瘤。治疗包括使用免疫治疗剂以及溶瘤病毒，结果各不相同，原因尚不清楚。为了更好地了解可能有助于预测治疗结果的机制，我们评估了由干扰素基因刺激物(STING)控制的选定卵巢癌细胞系中的先天性免疫信号，该刺激物控制着自身或病毒DNA触发的细胞因子的产生。我们的结果表明，在大多数被检测的卵巢癌细胞中，STING依赖的信号转导存在习惯性缺陷，通常是通过表观遗传过程抑制STING和/或环二核苷酸(CDN)酶cGMP-AMP合成酶(CGAS)的表达。然而，需要RIG-I/MDA5的非刺痛、dsRNA激活的先天性免疫细胞因子的产生在很大程度上没有受到影响。这些缺陷使卵巢癌细胞能够避免DNA损伤介导的细胞因子的产生，这将提醒免疫监控系统。STIN信号的缺失也使卵巢癌细胞在体外和体内对病毒溶瘤伽马34.5缺失的HSV1(单纯疱疹病毒)感染高度敏感。意义：在肿瘤中评估STIN信号可能有助于预测疾病转归，并可能决定肿瘤病毒和其他类型癌症治疗的疗效。
Ovarian cancer is the sixth most prevalent cancer in women and the most lethal of the gynecologic malignancies. Treatments have comprised the use of immunotherapeutic agents as well as oncolytic viruses, with varying results for reasons that remain to be clarified. To better understand the mechanisms that may help predict treatment outcome, we have evaluated innate immune signaling in select ovarian cancer cell lines, governed by the Stimulator of Interferon Genes (STING), which controls self or viral DNA-triggered cytokine production. Our results indicate that STING-dependent signaling is habitually defective in majority of ovarian cancer cells examined, frequently through the suppression of STING and/or the cyclic dinucleotide (CDN) enzyme Cyclic GMP-AMP synthase (cGAS) expression, by epigenetic processes. However, STING-independent, dsRNA-activated innate immune cytokine production, which require RIG-I/MDA5, were largely unaffected. Such defects enabled ovarian cancer cells to avoid DNA damage-mediated cytokine production, which would alert the immunosurveillance system. Loss of STING signaling also rendered ovarian cancer cells highly susceptible to viral oncolytic gamma 34.5 deleted-HSV1 (Herpes simplex virus) infection in vitro and in vivo.Implications: STING signaling evaluation in tumors may help predict disease outcome and possibly dictate the efficacy of oncoviral and other types of cancer therapies.