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IL-6 通过诱导SOCS3表达缺失促进乳腺癌MDSCs 浸润和免疫抑制活性[J].程亚楠,蒋蒙蒙,张文文,刘芃芃,张蕊,于津浦.中国肿瘤生物治疗杂志,2018,(9):865~871.
IL-6 通过诱导SOCS3表达缺失促进乳腺癌MDSCs 浸润和免疫抑制活性    点此下载全文    点此浏览HTML全文
程亚楠  蒋蒙蒙  张文文  刘芃芃  张蕊  于津浦
天津医科大学肿瘤医院 a.肿瘤分子诊断中心;b.免疫学研究室国家肿瘤临床医学研究中心天津市肿瘤防治重点实验室天津市恶性肿瘤临床医学研究中心,天津 300060
基金项目:国家自然科学基金资助项目(No.81472473、81272360);国家科技支撑计划资助项目(No.2015BAI12B15);天津市科技计划资助项目(No.13ZCZCSY20300);天津医科大学肿瘤医院资助项目(No.1407)
DOI:10.3872/j.issn.1007-385X.2018.09.004
摘要:
      目的:探讨髓系来源抑制细胞(myeloid-derived suppressor cells,MDSCs)通过IL-6 诱导STAT3/IDO信号通路活化对T细胞的免疫抑制作用及其分子机制。方法:收集天津医科大学肿瘤医院2015 年11 月至2016 年2 月收治的20 例乳腺癌患者肿瘤组织及其癌旁组织和40 例健康供者的外周血样本。免疫磁珠技术分选肿瘤组织中的CD33+和健康供者外周血中的CD33+和CD14+细胞,CD33+体外与乳腺癌细胞系MDA-MB-231 共孵诱导MDSCs生成。流式细胞术检测表型为CD45+CD13+CD33+CD14-CD15-的MDSCs 比例,Western blotting 检测细胞因子信号转导抑制因子1(suppressors of cytokine signalling 1,SOCS1)、SOCS3、JAK1、JAK2、TYK2、STAT1、STAT3 及其磷酸化水平,qRT-PCR 检测IL-6、SOCS1-3 的表达水平,CCK-8 法检测T 细胞增殖情况,Annexin V检测T 细胞凋亡,ELISA 检测T 细胞分泌的IL-10 和IFN-γ。结果:20 例乳腺癌组织中均有不同程度的MDSCs浸润(15.3%~58.1%),平均为(29.82±11.46)%;IL-6high组MDSCs浸润比例明显高于IL-6low组[ (13.75±3.44)% vs(4.31±1.50)%,P<0.05],且IL-6 表达与MDSCs浸润呈正相关(R2=0.4399,P<0.01)。体外实验发现肿瘤源性IL-6 明显促进体外MDSCs的生成和免疫抑制活性,该过程可被IL-6 信号的阻断所逆转(P<0.05);同样发现在体外诱导的MDSCs中SOCS3 表达缺失,阻断IL-6 后,以上过程被明显抑制(P< 0.05)。结论:乳腺癌来源的IL-6 刺激MDSCs中JAK/STAT信号通路的持续活化和SOCS3 的表达缺失,进而促进MDSCs的浸润、生成和免疫活性。因此IL-6 信号通路可以作为削弱MDSCs生成和逆转MDSCs活性的治疗靶点。
关键词:乳腺癌  髓系来源抑制细胞  白介素-6  JAK/STAT信号通路  细胞因子信号转导抑制因子
IL-6 promotes MDSCs infiltration and immunosuppression in breast cancer by inducing SOCS3 deficiency    Download Fulltext
CHENG Yanan  JIANG Mengmeng  ZHANG Wenwen  LIU Pengpeng  ZHANG Rui  YU Jinpu
a.Cancer Molecular Diagnostics Center; b. Department of Immunology, Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Clinical Research Center for Malignant Cancer of Tianjin City,Tianjin 300060, China
Fund Project:Project supported by the National Natural Science Foundation of China(No.81472473, No.81272360), the National Science and Technology Pillar Program (No.2015BAI12B15), the Tianjin Municipal Commission of Science and Technology Key Research Program (No.13ZCZCSY20300), and the Tianjin Medical University Cancer Institute and Hospital Research Program(No.1407)
Abstract:
      Objective: To investigate the immunosuppressive effect and underlying molecular mechanisms of Myeloid-derived suppressor cells (MDSCs) on T cells activity through IL-6activatingSTAT3/IDO signaling pathway. Methods: Twenty pairs of cancer tissues and the corresponding adjacent normal tissues from breast cancer patients treated at Tianjin Medical University Cancer Institute and Hospital from November 2015 to February 2016 were collected for this study; in the meanwhile, peripheral blood samples from 40 healthy donorswere also collected.CD33+ cells in tumor tissues and CD33 + CD14 + cells in peripheral blood of helthy donors were sorted out with MicroBeads technology. CD33+cells were in vitro co-cultured with breast cancer cell line MDA-MB-231 to induce MDSCs. Flow cytometry was used to detect the proportion of CD45+CD13+CD33+CD14-CD15- MDSCs.Western Blotting was used to detect the expression ofSOCS1,SOCS3, JAK1, JAK2, TYK2, STAT1, STAT3 and their phosphorylation levels. qRT-PCR was used to detect the expression of IL-6 and SOCS1-3. CCK8 was used to detect the T cell proliferation.Annexin V staining was used to detect T cell apoptosis. ELISA was used to detect IL-10 and IFN-γ secreted by T cells. Results: There were MDSCs infiltration in all 20 cases of breast cancer tissues for different levels (15.3%~58.1%), with a mean level of (29.82 ±11.46%); the infiltration of IL-6high group was significantly higher than that of the IL-6 low group [ (13.75±3.44)% vs(4.31±1.50)%,P<0.05], indicating that IL-6 expression was positively correlated with MDSCs infiltration (R2=0.4399, P<0.01). In vitro experiments showed that tumor-derived IL-6 significantly promoted the generation and immunosuppressive activity of MDSCs (P<0.05), which could be reversed by the blocking of IL-6. In the meanwhile, the expression of SOCS3 in MDSCs that induced in vitro was absent,which can be inhibited by blocking IL-6 (P<0.05). Conclusion: The study has demonstrated that tumor-derived IL-6 stimulates the continuous activation of the JAK/STAT signaling pathway and the absence of SOCS3 expression in MDSCs, thereby promoting the infiltration,generation and immunological activity of MDSCs. Therefore, IL-6 signaling pathway can be used as therapeutic target to weaken MDSCs generation and reverse MDSCs activity.
Keywords:breast cancer  myeloid-derived suppressor cells (MDSCs)  IL-6  JAK/STATsignaling pathway  suppressors of cytokine signalling(SOCS)
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