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结直肠癌肿瘤相关成纤维细胞对免疫治疗和肝转移的影响

王晓庆 龙杰 王菲 廉哲雄

引用本文:
Citation:

结直肠癌肿瘤相关成纤维细胞对免疫治疗和肝转移的影响

DOI: 10.12449/JCH240618
基金项目: 

国家自然科学基金青年科学基金 (82303785);

国家自然科学基金青年科学基金 (32100720)

利益冲突声明:本文不存在任何利益冲突。
作者贡献声明:王晓庆主要负责文章实验开展,数据分析,论文撰写;龙杰负责文章指导,数据分析,论文修改;王菲负责文章指导,论文修改;廉哲雄负责文章指导并最终定稿。
详细信息
    通信作者:

    廉哲雄, zxlian@gdph.org.cn (ORCID: 0000-0002-9525-1421)

Impact of cancer-associated fibroblasts on immunotherapy and liver metastasis in colorectal cancer

Research funding: 

Young Scientists Fund of the National Natural Science Foundation of China (82303785);

Young Scientists Fund of the National Natural Science Foundation of China (32100720)

More Information
    Corresponding author: LIAN Zhexiong, zxlian@gdph.org.cn (ORCID: 0000-0002-9525-1421)
  • 摘要:   目的  探讨结直肠癌(CRC)中肿瘤相关成纤维细胞(CAF)对免疫治疗和肝转移的影响。  方法  从基因表达数据库(GEO)中下载错配修复缺陷(MMRd)的CRC患者相关的单细胞测序数据(GSE205506),利用R软件对原始测序数据进行预处理,建立CAF亚群降维图,并根据每个亚群的标志性基因对亚群进行命名,使用GraphPad对每种亚群的比例进行统计,分析CRC患者在程序性死亡受体1(PD-1)免疫治疗前后以及治疗后病理完全缓解(pCR)与病理未完全缓解(non-pCR)患者中具有明显差异的关键亚群,对关键亚群进行差异基因分析和基因通路富集分析,利用肿瘤基因组图谱(TCGA)数据库对关键CAF亚群的标志性基因进行预后生存分析,通过RNA测序数据对CRC肝转移患者原发灶中关键CAF亚群进行评分和比例计算。符合正态分布的计量资料两组间比较采用成组t检验,Kaplan-Meier法绘制生存曲线,Log-rank检验比较生存率。利用CellPhoneDB软件分析成纤维细胞亚群与肿瘤细胞间的受配体相互作用,并通过体外细胞实验验证关键配体分子NRG1对CRC细胞迁移侵袭能力的影响。  结果  CRC患者经过PD-1免疫治疗后,F6_MMP1+CAF比例减少(P<0.001),但这种减少只发生在免疫治疗后完全缓解的患者中,F6_MMP1+CAF与肿瘤迁移和侵袭相关的基因及信号通路表达上调,此外,F6_MMP1+CAF在CRC肝转移患者肿瘤组织中明显增多(P<0.000 1)。F6_MMP1+CAF表达的NRG1作为配体与肿瘤细胞表达的ERBB3受体相互作用,体外实验证明NRG1通过激活ERBB信号通路促进肿瘤细胞的迁移和侵袭(P<0.05)。  结论  F6_MMP1+CAF可能影响CRC患者PD-1免疫治疗的效果,并在促进CRC发生肝转移过程中发挥重要作用,F6_MMP1+CAF及产生的促肿瘤转移的NRG1或许可以作为潜在的CRC治疗靶点及预后标志物。

     

  • 图  1  F6_MMP1+CAF影响免疫治疗的效果

    注: a,CRC成纤维细胞降维图; b,PD-1免疫治疗前后CAF亚群降维图;c,各亚群标志性基因展示;d,PD-1免疫治疗前后各CAF亚群所占比例;e,未治疗和治疗后完全缓解以及不完全缓解组中各CAF亚群所占比例。

    Figure  1.  F6_MMP1+CAFs influence response to immunotherapy

    图  2  F6_MMP1+CAF与患者预后不良及肿瘤发展有关

    注: a,火山图展示F6_MMP1+CAF和其他CAF差异基因;b,CRC患者中表达MMP1、MMP3、WNT5A基因评分高低与患者总体生存率的关系;c,各CAF亚群与肿瘤细胞配受体相互作用分析;d,各CAF亚群基因通路富集展示。

    Figure  2.  F6_MMP1+CAFs are associated with poor prognosis and tumor progression

    图  3  F6_MMP1+CAF可能与CRC发生肝转移过程密切相关

    注: a,F6_MMP1高表达基因展示图;b,RNA测序数据库GSE49355中CRC肝转移患者肠道正常组织和原发灶肿瘤组织中F6_MMP1评分和比例配对统计,CLMN:CRC肝转移患者肠道正常组织,CLMT:CRC肝转移患者肠道肿瘤组织;c,RNA测序数据库GSE50760中CRC肝转移患者正常组织和原发灶肿瘤组织中F6_MMP1评分和比例配对统计;d,RNA测序数据库GSE81558和GSE68468中CRC肝转移患者正常组织和原发灶肿瘤组织中F6_MMP1评分统计。

    Figure  3.  F6_MMP1+CAFs may be related to the liver metastasis of CRC

    图  4  F6_MMP1+CAF表达的NRG1激活ERBB通路促进CRC的迁移和侵袭

    注: a、b,Transwell实验证明NRG1对CACO2迁移和侵袭能力的影响(×40);c、d,划痕实验证明NRG1通过结合ERBB3发挥作用。

    Figure  4.  NRG1 expressed by F6_MMP1+CAFs activates ERBBs pathway and promotes CRC migration and invasion

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  • 收稿日期:  2023-12-27
  • 录用日期:  2024-01-19
  • 出版日期:  2024-06-25
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