T cell-intrinsic STING signaling promotes regulatory T cell induction and immunosuppression by upregulating FOXP3 transcription in cervical cancer.
T cell-intrinsic STING signaling promotes regulatory T cell induction and immunosuppression by upregulating FOXP3 transcription in cervical cancer.
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T细胞固有的STING信号通过上调宫颈癌中FOXP 3转录来促进调节性T细胞诱导和免疫抑制。
DOI：
10.1136/jitc-2022-005151
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发表时间：
2022-09
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
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作者：
干扰素基因刺激物 (STING) 是源自微生物和宿主细胞的细胞质双链 DNA 的先天免疫传感器。肿瘤微环境中胞浆 DNA-STING 通路的激活通常与对肿瘤更强大的适应性免疫反应有关，然而 STING 在调节性 T 细胞中的细胞内功能很大程度上未知。在本研究中，我们旨在探讨细胞内 STING 激活对宫颈癌 (CC) 微环境中调节性 T 细胞诱导 (iTreg) 的贡献。血液样本和肿瘤标本取自 CC 患者。通过免疫组织化学检测瘤内 STING、CCL22、CD8 和叉头盒 P3 (FOXP3) 的表达水平。生成T细胞特异性STING条件敲除小鼠（CD4-Cre/STINGflox/flox，TKO），并研究同基因TC-1肿瘤模型。通过离体实验、免疫印迹和定量PCR研究不同处理下人和鼠iTreg的分化和分子调控通路。从 CC 细胞系中分离出肿瘤相关外泌体 (T-EXO)，并通过 ELISA 和蛋白质印迹分析鉴定外泌体内容物。在体外细胞培养中测试了 T-EXO 对 T 细胞分化的影响。肿瘤组织中 STING、CCL22 水平、FOXP3+ 细胞增加但 CD8+ 细胞减少预示着生存率较差。与野生型 (WT) 小鼠相比，携带肿瘤的 CD4-Cre-STINGflox/flox (TKO) 小鼠表现出较慢的肿瘤生长趋势以及较少的 FOXP3+ 细胞，但肿瘤组织中的 CD8+ 细胞比例较高。 STING 信号的激活与 T 细胞受体、白细胞介素 2 受体和转化生长因子 β (TGF-β) 信号协同作用，在体外促进 WT 和 IFNAR−/− 小鼠而非 TKO 或 IRF3−/− 小鼠的人类和小鼠 CD4+ 初始 T 细胞分化为 CD4+CD25highFOXP3+ iTreg。异位 STING、TBK1 或 IRF3 表达促进 iTreg 从人 CD4+ 初始 T 细胞分化。 T 细胞固有的 STING 激活通过 TBK1-IRF3 介导的 SMAD3 和 STAT5 磷酸化诱导 FOXP3 转录，不依赖于干扰素-β。在 CC 中，肿瘤来源的外泌体通过外泌体 TGF-β、环 GMP-AMP 合酶和 2’-3’-cGAMP 激活肿瘤浸润 T 细胞中的 STING 信号传导，导致 iTreg 扩增。这些发现强调了由肿瘤源性外泌体激活的 T 细胞固有 STING 信号介导的 iTreg 扩增的新机制，并为开发针对 CC 中 STING 信号的免疫治疗策略提供了理论依据。
Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic double-stranded DNA originating from microorganisms and host cells. The activation of cytosolic DNA-STING pathway in tumor microenvironments is usually linked to more robust adaptive immune responses to tumors, however the intracellular function of STING in regulatory T cells is largely unknown. In the present study, we aimed to explore the contribution of intracellular STING activation to regulatory T cell induction (iTreg) in cervical cancer (CC) microenvironments. Blood samples and tumor specimens were obtained from patients with CC. The intratumoral STING, CCL22, CD8 and forkhead box P3 (FOXP3) expression levels were measured by immunohistochemistry. T cell-specific STING conditional knockout mice (CD4-Cre/STINGflox/flox, TKO) were generated, and syngeneic TC-1 tumor model were investigated. The differentiation and molecular regulatory pathway of human and murine iTreg under different treatments were investigated by ex vivo assays, immunoblotting and quantitative PCR. Tumor-associated exosomes (T-EXO) were isolated from CC cell lines and exosomal contents were identified by ELISA and Western blot analysis. The impact of T-EXO on T cell differentiation was tested in in vitro cell culture. Increased STING, CCL22 level, FOXP3+ cells but decreased CD8+ cells in tumor tissues predicted poor survival. Tumor-bearing CD4-Cre-STINGflox/flox (TKO) mice displayed slower tumor growth tendencies as well as fewer FOXP3+ cells but higher CD8+ cell proportion in tumor tissues than wild-type (WT) mice. Activating of STING signaling cooperated with T cell receptor, interleukin-2 receptor and transforming growth factor-beta (TGF-β) signals to promote CD4+CD25highFOXP3+ iTreg differentiation from both human and murine CD4+-naïve T cells from WT and IFNAR−/− mice but not TKO or IRF3−/− mice in vitro. Ectopic STING, TBK1 or IRF3 expression promoted iTreg differentiation from human CD4+-naïve T cells. T cell-intrinsic STING activation induced FOXP3 transcription through TBK1-IRF3-mediated SMAD3 and STAT5 phosphorylation independent of interferon-β. In CC, tumor-derived exosomes activated STING signaling in tumor-infiltrated T cells by exosomal TGF-β, cyclic GMP-AMP synthase and 2’-3’-cGAMP, leading to iTreg expansion. These findings highlight a novel mechanism for iTreg expansion mediated by tumor-derived exosome-activated T cell-intrinsic STING signal, and provide a rationale for developing immunotherapeutic strategies targeting STING signal in CC.
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DOI：
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发表时间：
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影响因子：
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DOI：
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2020-11-02
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