MMP14阳性肿瘤相关成纤维细胞亚群通过外泌体tsRNA-10522抑制食管癌PD-1免疫疗法的机制

IF 3.9 4区 生物学 Q1 GENETICS & HEREDITY Functional & Integrative Genomics Pub Date : 2024-10-08 DOI:10.1007/s10142-024-01447-3
Juzheng Wang, Chunlong Zheng, Jiayu Lu, Xinyao Xu, Guangyu Xiang, Jiahe Li, Jipeng Zhang, Xiaorong Mu, Qiang Lu
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引用次数: 0

摘要

食管癌(EC)继续对健康构成重大威胁。癌症相关成纤维细胞(CAFs)是肿瘤微环境(TME)的重要组成部分,被视为潜在的治疗靶点。然而,它们在食管癌特有的肿瘤机制中的作用仍有待阐明。本研究采用免疫荧光染色法鉴定了MMP14+ CAFs和MMP14- CAFs。CD8 T细胞的细胞毒活性通过Western印迹和ELISA进行了评估。利用透孔试验评估了 MMP14+ CAFs 的迁移潜力。通过流式细胞术发现了食管鳞状细胞癌细胞系 KYSE30 的细胞凋亡。为了确定 MMP14+ CAFs 释放的重要 tsRNA,采用了 tsRNA-seq 技术。我们的研究确定了接受PD-1免疫疗法的EC的两个亚群:MMP14+ CAFs和MMP14- CAFs。MMP14+ CAFs表现出更强的迁移能力,并释放出更多与癌症相关的炎症因子。通过外泌体,这些CAFs可能会阻止抗PD-1处理的CD8 T细胞产生细胞毒性。此外,来自 MMP14+ CAFs 的外泌体 tsRNA 主要靶向与癌症相关的信号通路。值得注意的是,研究发现 tsRNA-10522 在抑制 CD8 T 细胞肿瘤细胞死亡方面发挥了关键作用。在 PD-1 免疫疗法期间,外泌体 tsRNA-10522 对 CD8 T 细胞的肿瘤细胞杀伤作用会被 EC 微环境中称为 MMP14+ CAFs 的细胞亚群抑制。这降低了 PD-1 免疫疗法对心血管疾病的疗效。我们的研究结果证明了接受PD-1免疫疗法的EC内的MMP14+ CAFs具有抑制功能,从而有望将MMP14+ CAFs作为接受PD-1免疫疗法的EC的预测指标。
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The mechanism of MMP14-positive tumor-associated fibroblast subsets in inhibiting PD-1 immunotherapy for esophageal cancer through exosomal tsRNA-10522
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来源期刊
CiteScore
3.50
自引率
3.40%
发文量
92
审稿时长
2 months
期刊介绍: Functional & Integrative Genomics is devoted to large-scale studies of genomes and their functions, including systems analyses of biological processes. The journal will provide the research community an integrated platform where researchers can share, review and discuss their findings on important biological questions that will ultimately enable us to answer the fundamental question: How do genomes work?
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