Abstract
BackgroundTumor-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.MethodsIn 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.ResultsBased 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.ConclusionsTEXscore capturing tumor-derived exosome features might be a robust biomarker for prognosis and treatment responses in independent cohorts.
Highlights
Exosomes are 30–150 nm-sized extracellular vesicles of endosomal origin that inherit constituents from multiple cell types [1]
The Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the selected genes revealed that Tumor-derived exosomes (TEXs) genes were enriched in pathways associated with exosome formation and release
TEXscores of cancer cells increased at progressive disease (PD) status when tumor acquired drug resistance, compared with the relatively low TEXscores at the time point of pre-treatment (Pre) and partial response (PR)/stable disease (SD) statuses, implying an association between TEXscore and cancer progression undergoing treatment (Kruskal–Wallis test, P ≤ 2e−16; Fig. 1B, C)
Summary
Exosomes are 30–150 nm-sized extracellular vesicles of endosomal origin that inherit constituents from multiple cell types [1]. Relying on the plentiful cargos including proteins, nucleic acids, lipids, and metabolites, exosomes participate in intercellular communication and further influence the surrounding microenvironment in both. Increasing evidence indicates that tumor-derived exosomes (TEXs) emerge as a vital modulator in various tumorigenesis processes, including tumor invasion, metastasis, and treatment resistance [5]. TEXs are taken up by immune cells and stromal cells that constitute the tumor microenvironment (TME), thereby changing TME infiltration pattern and affecting cell behavior [6, 7]. Tumor-derived exosomes (TEXs) are involved in tumor progression and the immune modulation process and mediate intercellular communication in the tumor microenvironment. Exosomes are considered promising liquid biomarkers for disease diagnosis, it is difficult to discriminate TEXs and to develop TEX-based predictive biomarkers
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