转录因子MESP1通过抑制cGAS-STING通路促进三阴性乳腺癌免疫逃逸的机制研究

批准号:
82002792
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
肖毅
依托单位:
学科分类:
肿瘤免疫治疗
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
肖毅
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中文摘要
三阴性乳腺癌预后差,缺乏治疗靶点,是乳腺癌临床治疗的难点。前期研究中,我们运用免疫组学技术分析三阴性乳腺癌肿瘤微环境的异质性,将其分为两类适应性免疫细胞浸润较少的“冷肿瘤”和一类适应性免疫细胞浸润较多的“热肿瘤”,“热肿瘤”预后更好并可能对免疫治疗敏感。因此,寻找三阴性乳腺癌中“冷肿瘤”的驱动因素,尝试肿瘤“冷”转“热”具有重要研究价值。预实验中我们发现转录因子MESP1拷贝数扩增导致其高表达可能是驱动“冷肿瘤”形成的关键因素,MESP1可负向调控STING分子的表达。据此我们提出假设:MESP1扩增通过抑制cGAS-STING通路,进而抑制免疫反应的启动,导致三阴性乳腺癌肿瘤微环境T细胞浸润降低。我们将以此为研究线索,利用乳腺癌细胞系、小鼠原位移植瘤模型、临床样本,进一步探索MESP1调控STING分子的具体机制,探索三阴性乳腺癌“冷”转“热”的策略,最终为临床治疗三阴性乳腺癌提供线索。
英文摘要
Triple-negative breast cancer (TNBC) is a subset of refractory breast cancer lacking therapeutic targets and having poor prognosis. In previous studies, we conducted immunogenomic analysis to explore the heterogeneity of tumor microenvironment (TME) among different TNBC samples. We classified the TME of TNBC into two distinct types of "cold tumors" with few adaptive immune cells infiltration and one type of "hot tumor" with abundant adaptive immune cells infiltration. TNBC patients with "hot tumors" are more sensitive to immune checkpoint inhibitors and have better prognosis. Therefore, we need to explore the drivers resulting in the formation of "cold tumor" in TNBC and try to transform "cold tumor" into "hot tumor". In this study, we found that the copy number amplification of the transcription factor MESP1 was a potential driver of "cold tumor", decreasing the immune cells infiltration of TNBC through negatively regulating cGAS-STING pathway. In further study, we will take advantage of breast cancer cell lines, animal models and clinical samples to explore the mechanism of MESP1 regulating cGAS-STING pathway. Based on this project, we hope to reveal the role of MESP1 amplification in regulating the TME of TNBC, to explore the strategy of transforming "cold tumor" into "hot tumor" and to provide clinical clues for TNBC treatment.
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专利列表
DOI:10.1136/jitc-2021-002528
发表时间:2021-07
期刊:Journal for immunotherapy of cancer
影响因子:10.9
作者:Wu SY;Xiao Y;Wei JL;Xu XE;Jin X;Hu X;Li DQ;Jiang YZ;Shao ZM
通讯作者:Shao ZM
DOI:10.20892/j.issn.2095-3941.2021.0676
发表时间:2022-04-05
期刊:CANCER BIOLOGY & MEDICINE
影响因子:5.5
作者:Ding, Rui;Xiao, Yi;Mo, Miao;Zheng, Ying;Jiang, Yi-Zhou;Shao, Zhi-Ming
通讯作者:Shao, Zhi-Ming
DOI:10.1016/j.omto.2022.02.003
发表时间:2022-03-17
期刊:Molecular therapy oncolytics
影响因子:--
作者:Ding JH;Xiao Y;Zhao S;Xu Y;Xiao YL;Shao ZM;Jiang YZ;Di GH
通讯作者:Di GH
DOI:10.1126/sciadv.adf0837
发表时间:2023-10-06
期刊:SCIENCE ADVANCES
影响因子:13.6
作者:Su, Guan-Hua;Xiao, Yi;You, Chao;Zheng, Ren-Cheng;Zhao, Shen;Sun, Shi-Yun;Zhou, Jia-Yin;Lin, Lu-Yi;Wang, He;Shao, Zhi-Ming;Gu, Ya-Jia;Jiang, Yi-Zhou
通讯作者:Jiang, Yi-Zhou
DOI:10.1016/j.cmet.2023.07.006
发表时间:2023
期刊:Cell Metabolism
影响因子:29
作者:Yi Xiao;Tian-Jian Yu;Ying Xu;Rui Ding;Yi-Ping Wang;Yi-Zhou Jiang;Zhi-Ming Shao
通讯作者:Zhi-Ming Shao
鸟苷二磷酸甘露糖通过降解BRCA2抑制三阴性乳腺癌同源重组修复的机制研究
- 批准号:82373167
- 项目类别:面上项目
- 资助金额:49万元
- 批准年份:2023
- 负责人:肖毅
- 依托单位:
国内基金
海外基金
