肿瘤来源外泌体特征的单细胞分析与预后和免疫治疗反应相关。
Single-cell analysis of a tumor-derived exosome signature correlates with prognosis and immunotherapy response.
机构信息
Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
出版信息
J Transl Med. 2021 Sep 8;19(1):381. doi: 10.1186/s12967-021-03053-4.
BACKGROUND
Tumor-derived exosomes (TEXs) are involved in tumor progression and the immune modulation process and mediate intercellular communication in the tumor microenvironment. Although exosomes are considered promising liquid biomarkers for disease diagnosis, it is difficult to discriminate TEXs and to develop TEX-based predictive biomarkers.
METHODS
In this study, the gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database, IMvigor210 cohorts, and six independent Gene Expression Omnibus datasets. A TEXs-associated signature named TEXscore was established to predict overall survival in multiple cancer types and in patients undergoing immune checkpoint blockade therapies.
RESULTS
Based on exosome-associated genes, we first constructed a tumor-derived exosome signature named TEXscore using a principal component analysis algorithm. In single-cell RNA-sequencing data analysis, ascending TEXscore was associated with disease progression and poor clinical outcomes. In the TCGA Pan-Cancer cohort, TEXscore was elevated in tumor samples rather than in normal tissues, thereby serving as a reliable biomarker to distinguish cancer from non-cancer sources. Moreover, high TEXscore was associated with shorter overall survival across 12 cancer types. TEXscore showed great potential in predicting immunotherapy response in melanoma, urothelial cancer, and renal cancer. The immunosuppressive microenvironment characterized by macrophages, cancer-associated fibroblasts, and myeloid-derived suppressor cells was associated with high TEXscore in the TCGA and immunotherapy cohorts. Besides, TEXscore-associated miRNAs and gene mutations were also identified. Further experimental research will facilitate the extending of TEXscore in tumor-associated exosomes.
CONCLUSIONS
TEXscore capturing tumor-derived exosome features might be a robust biomarker for prognosis and treatment responses in independent cohorts.
背景
肿瘤来源的外泌体（TEXs）参与肿瘤进展和免疫调节过程，并在肿瘤微环境中介导细胞间通讯。尽管外泌体被认为是疾病诊断有前途的液体生物标志物，但很难区分 TEXs 并开发基于 TEX 的预测性生物标志物。
方法
本研究从癌症基因组图谱（TCGA）数据库、IMvigor210 队列和六个独立的基因表达综合数据集收集了基因表达谱和临床信息。建立了一个名为 TEXscore 的 TEXs 相关特征，用于预测多种癌症类型和接受免疫检查点阻断治疗的患者的总生存期。
结果
基于外泌体相关基因，我们首先使用主成分分析算法构建了一个名为 TEXscore 的肿瘤源性外泌体特征。在单细胞 RNA-seq 数据分析中，TEXscore 升高与疾病进展和不良临床结局相关。在 TCGA 泛癌队列中，TEXscore 在肿瘤样本中升高，而在正常组织中则降低，因此可作为区分癌症与非癌症来源的可靠生物标志物。此外，TEXscore 在 12 种癌症类型中与总生存期较短相关。TEXscore 在黑色素瘤、尿路上皮癌和肾细胞癌的免疫治疗反应预测中具有很大的潜力。TCGA 和免疫治疗队列中，TEXscore 与巨噬细胞、癌相关成纤维细胞和髓系来源的抑制细胞等免疫抑制微环境相关。此外，还确定了与 TEXscore 相关的 miRNA 和基因突变。进一步的实验研究将有助于在肿瘤相关外泌体中扩展 TEXscore。
结论
TEXscore 捕获肿瘤源性外泌体的特征可能是独立队列中预后和治疗反应的强大生物标志物。
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