整合的单细胞和大量RNA-seq分析确定了结直肠癌癌症的预后T细胞特征-动脉网

Integrated single-cell and bulk RNA-seq analysis identifies a prognostic T-cell signature in colorectal cancer

Nature 等信源发布 2024-08-30 06:40

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AbstractColorectal cancer (CRC) is a major contributor to global morbidity and mortality, necessitating more effective therapeutic approaches. T cells, prominent in the tumor microenvironment, exert a crucial role in modulating immunotherapeutic responses and clinical outcomes in CRC. This study introduces a pioneering method for characterizing the CRC immune microenvironment using single-cell sequencing data.

摘要结直肠癌（CRC）是全球发病率和死亡率的主要原因，需要更有效的治疗方法。在肿瘤微环境中突出的T细胞在调节CRC的免疫治疗反应和临床结果中发挥关键作用。这项研究介绍了一种使用单细胞测序数据表征CRC免疫微环境的开创性方法。

Unlike previous approaches, which focused on individual T-cell signature genes, we utilized overall infiltration levels of colorectal cancer signature T-cells. Through weighted gene co-expression network analysis, Lasso regression, and StepCox analysis, we developed a prognostic risk model, TRGS (T-cell related genes signatures), based on six T cell-related genes.

与以前专注于单个T细胞特征基因的方法不同，我们利用了结直肠癌特征性T细胞的总体浸润水平。通过加权基因共表达网络分析，Lasso回归和StepCox分析，我们基于六个T细胞相关基因开发了一个预后风险模型TRGS（T细胞相关基因签名）。

Multivariate Cox analysis identified TRGS as an independent prognostic factor for CRC, showcasing its superior predictive efficacy compared to existing immune-related prognostic models. Immunoreactivity analysis revealed higher Immunophenoscore and lower Tumor Immune Dysfunction and Exclusion scores in the low-risk group, indicating potential responsiveness to immune checkpoint inhibitor therapy.

多变量Cox分析将TRGS鉴定为CRC的独立预后因素，与现有的免疫相关预后模型相比，显示出其优越的预测功效。免疫反应性分析显示，低风险组的免疫表型评分较高，肿瘤免疫功能障碍和排除评分较低，表明对免疫检查点抑制剂治疗的潜在反应性。

Additionally, patients in the low-risk group demonstrated heightened sensitivity to 5-fluorouracil-based chemotherapy regimens. In summary, TRGS emerges as a standalone prognostic biomarker for CRC, offering insights to optimize patient responses to immunotherapy and chemotherapy, thereby laying the groundwork for personalized tumor management strategies..

此外，低风险组患者对基于5-氟尿嘧啶的化疗方案表现出更高的敏感性。总之，TRGS作为CRC的独立预后生物标志物出现，为优化患者对免疫疗法和化疗的反应提供了见解，从而为个性化肿瘤管理策略奠定了基础。。

IntroductionColorectal cancer (CRC) stands as the third most prevalent malignancy globally, ranking second in mortality1,2, thereby posing substantial therapeutic challenges and an economic burden. Despite advancements in early CRC screening leading to improved 5 years survival rates, a subset of patients still presents at stage IV, resulting in a dismal prognosis3.

引言结直肠癌（CRC）是全球第三大最常见的恶性肿瘤，死亡率排名第二1,2，因此带来了巨大的治疗挑战和经济负担。尽管早期CRC筛查取得了进展，导致5年生存率提高，但仍有一部分患者处于IV期，导致预后不佳3。

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable therapeutic efficacy in diverse solid tumors, establishing them as the primary treatment for microsatellite instability-high (MSI-H) metastatic CRC4. However, given that this patient subset constitutes less than 5% of all CRC cases5, there is a critical need to identify more efficient biomarkers to guide the application of ICIs in colorectal cancer.The tumor microenvironment (TME) plays an important role in tumors, mainly in terms of tumor progression, angiogenesis, tumor metastasis, and influencing treatment outcome6,7,8,9.

免疫检查点抑制剂（ICI）已在多种实体瘤中显示出显着的治疗效果，将其确立为微卫星不稳定性高（MSI-H）转移性CRC4的主要治疗方法。然而，鉴于该患者亚群占所有CRC病例的不到5%，因此迫切需要鉴定更有效的生物标志物来指导ICI在结直肠癌中的应用。肿瘤微环境（TME）在肿瘤中起着重要作用，主要在肿瘤进展，血管生成，肿瘤转移和影响治疗结果方面6,7,8,9。

TME encompasses diverse cellular components such as immune cells, stromal cells, and non-cellular components including extracellular matrix molecules (ECM) and soluble signaling molecules10. Among these, T cells, including CD4+ and CD8+ T cells, represent the primary immune cells exerting anti-tumor activity11.

TME包括多种细胞成分，如免疫细胞，基质细胞和非细胞成分，包括细胞外基质分子（ECM）和可溶性信号分子10。其中，包括CD4+和CD8+T细胞在内的T细胞代表了发挥抗肿瘤活性的原代免疫细胞11。

After antigen-presenting cells present tumor cell antigens to T cells, activating them, the activated T cells infiltrate the tumor vicinity to exert cytotoxic effects on tumor cells12. However, tumor cells can evade immune surveillance through various mechanisms, such as HLA-I loss13, expression of immune checkpoint molecules14, or inhibitory effects from other cells in the microenvironment15,16.

在抗原呈递细胞将肿瘤细胞抗原呈递给T细胞并激活它们后，活化的T细胞浸润肿瘤附近以对肿瘤细胞发挥细胞毒性作用12。然而，肿瘤细胞可以通过各种机制逃避免疫监视，例如HLA-I丢失13，免疫检查点分子的表达14或微环境中其他细胞的抑制作用15,16。

Although more studies are focusing on a specific single T cell, few studies have been reported on overall T cells infiltra.

尽管更多的研究集中在特定的单个T细胞上，但很少有关于整体T细胞浸润的研究报道。

Data availability

数据可用性

The raw data utilized in our study were obtained from the TCGA dataset (https://portal.gdc.cancer.gov/) and the GEO dataset (https://www.ncbi.nlm.nih.gov/). Specifically, TCGA accession numbers for our study are TCGA-COAD and TCGA-READ, while GEO accession numbers are GSE39582, GSE38832, GSE132465, GSE28702, GSE19860, and GSE45404.

我们研究中使用的原始数据来自TCGA数据集(https://portal.gdc.cancer.gov/)和GEO数据集(https://www.ncbi.nlm.nih.gov/)。具体而言，我们研究的TCGA登录号是TCGA-COAD和TCGA-READ，而GEO登录号是GSE39582，GSE38832，GSE132465，GSE28702，GSE19860和GSE45404。

The datasets analyzed and R language codes employed in the current study are accessible upon reasonable request from the corresponding author..

根据通讯作者的合理要求，可以访问当前研究中使用的数据集和R语言代码。。

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Download referencesAcknowledgementsThe authors thank researchers and contributors of the TCGA and GEO databases for their valuable efforts and contributions.Author informationAuthors and AffiliationsDepartment of General Surgery, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, People’s Republic of ChinaPeng Cui & Zhigang BaiBeijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, People’s Republic of ChinaHaibo WangBeijing Laboratory of Oral Health, Capital Medical University, Beijing, People’s Republic of ChinaHaibo WangAuthorsPeng CuiView author publicationsYou can also search for this author in.

下载参考文献致谢作者感谢TCGA和GEO数据库的研究人员和贡献者的宝贵努力和贡献。作者信息作者及所属单位首都医科大学北京友谊医院国家消化疾病临床研究中心消化健康国家重点实验室普外科，北京市西城区永安路95号，100050，中华人民共和国彭崔和白志刚肿瘤侵袭转移北京市重点实验室，首都医科大学生物化学与分子生物学系，中华人民共和国北京海波王北京市首都医科大学口腔健康实验室，中华人民共和国北京海波王作者彭崔维作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarHaibo WangView author publicationsYou can also search for this author in

PubMed Google ScholarZhigang BaiView author publicationsYou can also search for this author in

PubMed Google ScholarZhigang BaiView作者出版物您也可以在

PubMed Google ScholarContributionsP.C. and Z.G.B. conceptualized and designed the study. P.C. was responsible for data collection, analysis, and initial manuscript drafting. H.B.W. reviewed the statistical analysis and performed manuscript editing. Z.G.B. oversaw the project, contributed to manuscript editing, provided critical feedback, and supervised the study.

PubMed谷歌学术贡献SP。C、 Z.G.B.对这项研究进行了概念化和设计。P、 C.负责数据收集，分析和初稿起草。H、。Z、 G.B.监督该项目，为稿件编辑做出贡献，提供关键反馈，并监督研究。

All authors contributed to the critical revision of the manuscript and approved the final version for publication.Corresponding authorCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleCui, P., Wang, H. & Bai, Z. Integrated single-cell and bulk RNA-seq analysis identifies a prognostic T-cell signature in colorectal cancer.

转载和许可本文引用本文Cui，P.，Wang，H。＆Bai，Z。综合单细胞和大量RNA-seq分析确定了结直肠癌的预后T细胞特征。

Sci Rep 14, 20177 (2024). https://doi.org/10.1038/s41598-024-70422-6Download citationReceived: 24 March 2024Accepted: 16 August 2024Published: 30 August 2024DOI: https://doi.org/10.1038/s41598-024-70422-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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KeywordsColorectal cancerT cellImmune checkpoint inhibitorsPrognostic risk modelChemotherapy

关键词结直肠癌细胞免疫检查点抑制剂预后风险模型化疗

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