STING Contributes to Antiglioma Immunity via Triggering Type I IFN Signals in the Tumor Microenvironment
STING Contributes to Antiglioma Immunity via Triggering Type I IFN Signals in the Tumor Microenvironment
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DOI：
10.1158/2326-6066.cir-14-0099
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发表时间：
2014-12-01
影响因子：
10.1
通讯作者：
Okada, Hideho
中科院分区：
文献类型：
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作者：
Ohkuri, Takayuki;Ghosh, Arundhati;Okada, Hideho
尽管I型干扰素在抗病毒和抗肿瘤活性中发挥着关键作用，但I型干扰素如何在肿瘤微环境的无菌条件下产生并直接影响肿瘤浸润免疫细胞仍有待阐明。小鼠新生神经胶质瘤显示 I 型 IFN 信息表达增加，在小鼠中，CD11b(+) 脑浸润白细胞 (BIL) 是 I 型 IFN 的主要来源，其部分以 STING（IFN 基因刺激剂）依赖性方式诱导。因此，与野生型小鼠相比，患有神经胶质瘤的 StingGt/Gt 小鼠表现出更短的生存期和更低的 Ifns 表达水平。此外，StingGt/Gt小鼠的BIL显示CD11b(+) Gr-1(+)未成熟骨髓抑制细胞和CD25(+) Foxp3(+)调节性T细胞(Treg)增加，而产生IFNγ的CD8(+)T细胞减少。接受直接I型干扰素信号的CD4+和CD8+T细胞分别表现出较低程度的调节活性和较高水平的抗肿瘤活性。最后，肿瘤内注射 STING 激动剂（环二鸟苷酸单磷酸酯；c-di-GMP）可改善患有神经胶质瘤的小鼠的存活率，这与增强的 I 型 IFN 信号传导、Cxcl10 和 Ccl5 以及 T 细胞迁移到大脑中有关。与皮下 OVA 肽疫苗接种相结合，c-di-GMP 增加了 BIL 的 OVA 特异性细胞毒性并延长了其存活时间。这些数据表明，STING 通过增强肿瘤微环境中的 I 型 IFN 信号传导，对抗肿瘤免疫做出了重大贡献，并表明 STING 激动剂可能用于开发有效的免疫疗法，例如与抗原特异性疫苗接种相结合。 (C) 2014 年 AACR。
Although type I IFNs play critical roles in antiviral and antitumor activity, it remains to be elucidated how type I IFNs are produced in sterile conditions of the tumor microenvironment and directly affect tumor-infiltrating immune cells. Mouse de novo gliomas show increased expression of type I IFN messages, and in mice, CD11b(+) brain-infiltrating leukocytes (BIL) are the main source of type I IFNs that are induced partially in a STING (stimulator of IFN genes)-dependent manner. Consequently, glioma-bearing StingGt/Gt mice showed shorter survival and lower expression levels of Ifns compared with wild-type mice. Furthermore, BILs of StingGt/Gt mice showed increased CD11b(+) Gr-1(+) immature myeloid suppressor and CD25(+) Foxp3(+) regulatory T cells (Treg) and decreased IFN gamma-producing CD8(+)T cells. CD4(+) and CD8(+) T cells that received direct type I IFN signals showed lesser degrees of regulatory activity and increased levels of antitumor activity, respectively. Finally, intratumoral administration of a STING agonist (cyclic diguanylate monophosphate; c-di-GMP) improved the survival of glioma-bearing mice associated with enhanced type I IFN signaling, Cxcl10 and Ccl5, and T-cell migration into the brain. In combination with subcutaneous OVA peptide vaccination, c-di-GMP increased OVA-specific cytotoxicity of BILs and prolonged their survival. These data demonstrate significant contributions of STING to antitumor immunity via enhancement of type I IFN signaling in the tumor microenvironment and suggest a potential use of STING agonists for the development of effective immunotherapy, such as the combination with antigen-specific vaccinations. (C) 2014 AACR.