STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity
STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity
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DOI：
10.1073/pnas.1512832112
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发表时间：
2015-12-15
影响因子：
11.1
通讯作者：
Gilliet, Michel
中科院分区：
文献类型：
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作者：
Demaria, Olivier;De Gassart, Aude;Gilliet, Michel
自发的CD 8 T细胞反应发生在生长的肿瘤中，但通常效果不佳。了解驱动这些反应的分子和细胞机制是主要的兴趣，因为它们可以被利用来产生更有效的抗肿瘤免疫。因此，IFN基因刺激物（STING），一种参与胞质DNA传感的衔接分子，是在小鼠癌症模型中诱导抗肿瘤CD 8 T应答所必需的。在这里，我们发现通过肿瘤内注射环二核苷酸GMP-AMP（cGAMP）来加强STING的活化，有效地增强了抗肿瘤CD 8 T应答，导致黑色素瘤和结肠癌小鼠模型中注射的和对侧肿瘤的生长控制。cGAMP触发抗肿瘤免疫的能力通过PD 1和CTLA 4的阻断而进一步增强。STING依赖性抗肿瘤免疫，无论是在生长的肿瘤中自发诱导还是通过肿瘤内cGAMP注射诱导，都依赖于肿瘤微环境中产生的I型IFN。在对cGAMP注射的响应中，在小鼠黑素瘤模型和培养的人黑素瘤外植体的离体模型中，I型IFN的主要来源不是树突细胞，而是内皮细胞。类似地，内皮细胞而不是树突状细胞被发现是生长中的肿瘤中自发诱导的I型IFN的主要来源。这些数据确定了肿瘤血管系统在启动CD 8 T细胞抗肿瘤免疫中的意想不到的作用，并证明肿瘤内皮细胞可以靶向黑色素瘤的免疫治疗。
Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.