Integrity of the Antiviral STING-mediated DNA Sensing in Tumor Cells Is Required to Sustain the Immunotherapeutic Efficacy of Herpes Simplex Oncolytic Virus.
Integrity of the Antiviral STING-mediated DNA Sensing in Tumor Cells Is Required to Sustain the Immunotherapeutic Efficacy of Herpes Simplex Oncolytic Virus.
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肿瘤细胞中抗病毒STING介导的DNA感应的完整性是维持单纯疱疹溶瘤病毒免疫治疗效果所必需的。
DOI：
10.3390/cancers12113407
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发表时间：
2020-11-17
期刊：
影响因子：
5.2
通讯作者：
Zambrano N
中科院分区：
文献类型：
--
作者：
Froechlich G;Caiazza C;Gentile C;D'Alise AM;De Lucia M;Langone F;Leoni G;Cotugno G;Scisciola V;Nicosia A;Scarselli E;Mallardo M;Sasso E;Zambrano N
溶瘤病毒是癌症治疗中新兴的免疫疗法。天然免疫在溶瘤病毒抗肿瘤活性中的矛盾作用仍然是一个有争议的问题。依赖于STING的DNA感应轴被认为对病毒复制和癌细胞清除有害。因此，我们观察到肿瘤细胞中STING缺失与一种基于疱疹的溶瘤病毒裂解潜能提高有关。然而，感染溶瘤病毒的STING敲除癌细胞显示免疫原性受损，因为免疫原性细胞死亡未被正确触发。与这些观察结果一致，在小鼠同基因模型中产生的STING敲除肿瘤对溶瘤病毒与PD - 1阻断剂的联合治疗更具抗性。本研究证明了抗病毒免疫的抗肿瘤益处，并阐明了肿瘤细胞中STING缺失对溶瘤病毒疗法产生免疫抗性的机制。
癌细胞裂解和肿瘤免疫原性的二分作用被认为对有效的溶瘤病毒疗法至关重要，这表明天然抗病毒免疫反应是溶瘤病毒疗效的一个障碍。然而，新出现的证据正在改变这一观点。通过感知胞质DNA，环鸟苷酸 - 腺苷酸合酶（cGAS）和干扰素基因刺激因子（STING）轴既能对抗病毒传播，又能通过I型干扰素反应促进适应性免疫的激发。在本文中，我们在免疫健全的小鼠模型中，分析了在溶瘤病毒疗法和PD - 1免疫检查点阻断联合治疗方法中，STING介导的DNA感应在肿瘤内的功能。虽然在体外和体内都支持溶瘤性HER2重靶向单纯疱疹病毒1型（HSV - 1）裂解潜能增加，但STING敲除肿瘤显示出免疫抑制性肿瘤微环境的分子特征。这些特征相应地与已建立肿瘤模型中联合治疗的无效性相关。结果表明，STING敲除肿瘤抗病毒反应的受损虽然有利于病毒复制，但由于缺乏免疫原性细胞死亡以及STING敲除癌细胞无法促进抗肿瘤适应性免疫反应，无法引发足够的免疫治疗效果。因此，我们提出，肿瘤内的抗病毒STING对溶瘤病毒的免疫治疗效果具有重要作用。
Oncolytic viruses are emerging immunotherapeutics in cancer treatments. The conflicting role of innate immunity in the antitumor activity of oncolytic viruses is still a matter of debate. The STING-dependent DNA sensing axis is considered detrimental for viral replication and cancer cell clearance. Accordingly, we observed that STING loss in tumor cells was associated with improved lytic potential by a herpes-based oncolytic virus. However, STING-knockout cancer cells infected with the oncolytic virus showed impaired immunogenicity, as immunogenic cell death was improperly triggered. In agreement with these observations, STING-knockout tumors raised in a murine syngeneic model were more resistant to a combined treatment of the oncolytic virus with PD-1 blockade. The present study demonstrates the antitumor benefit of antiviral immunity and sheds lights on the mechanisms of immune resistance to oncovirotherapy exerted by STING-loss in tumor cells. The dichotomic contribution of cancer cell lysis and tumor immunogenicity is considered essential for effective oncovirotherapy, suggesting that the innate antiviral immune response is a hurdle for efficacy of oncolytic viruses. However, emerging evidence is resizing this view. By sensing cytosolic DNA, the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) axis can both counteract viral spread and contribute to the elicitation of adaptive immunity via type I interferon responses. In this paper, we analyzed the tumor-resident function of Sting-mediated DNA sensing in a combined approach of oncovirotherapy and PD-1 immune checkpoint blockade, in an immunocompetent murine model. While supporting increased lytic potential by oncolytic HER2-retargeted HSV-1 in vitro and in vivo, Sting-knockout tumors showed molecular signatures of an immunosuppressive tumor microenvironment. These signatures were correspondingly associated with ineffectiveness of the combination therapy in a model of established tumors. Results suggest that the impairment in antiviral response of Sting-knockout tumors, while favoring viral replication, is not able to elicit an adequate immunotherapeutic effect, due to lack of immunogenic cell death and the inability of Sting-knockout cancer cells to promote anti-tumor adaptive immune responses. Accordingly, we propose that antiviral, tumor-resident Sting provides fundamental contributions to immunotherapeutic efficacy of oncolytic viruses.
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影响因子：
7.2
作者：
Michaud M;Xie X;Bravo-San Pedro JM;Zitvogel L;White E;Kroemer G
通讯作者：
Kroemer G
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
6.7
作者：
Leoni, Valerio;Vannini, Andrea;Campadelli-Fiume, Gabriella
通讯作者：
Campadelli-Fiume, Gabriella
影响因子：
5.4
作者：
Menotti, Laura;Cerretani, Arianna;Campadelli-Fiume, Gabriella
通讯作者：
Campadelli-Fiume, Gabriella
DOI：
10.1073/pnas.1620433114
发表时间：
2017-01-31
影响因子：
11.1
作者：
Chamoto, Kenji;Chowdhury, Partha S.;Honjo, Tasuku
通讯作者：
Honjo, Tasuku