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Small Extracellular Vesicles in Pre-Therapy Plasma Predict Clinical Outcome in Non-Small-Cell Lung Cancer Patients.

ABSTRACT: The potential use of plasma-derived small extracellular vesicles (sEV) as predictors of response to therapy and clinical outcome in chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) was explored. sEV were isolated by size-exclusion chromatography from the plasma of 79 chemotherapy-naïve NSCLC patients and 12 healthy donors (HD). sEV were characterized with regard to protein content, particle size, counts by qNano, morphology by transmission electron microscopy, and molecular profiles by Western blots. PD-1 and PD-L1 expression on circulating immune cells was analysed by flow cytometry. Pre-treatment levels of total sEV protein (TEP) were correlated with overall (OS) and progression-free survival (PFS). The sEV numbers and protein levels were significantly elevated in the plasma of NSCLC patients compared to HD (p = 0.009 and 0.0001, respectively). Baseline TEP levels were higher in patients who developed progressive disease compared to patients with stable disease (p = 0.007 and 0.001, stage III and IV, respectively). Patient-derived sEV were enriched in immunosuppressive proteins as compared to proteins carried by sEV from HD. TEP levels were positively correlated with CD8⁺PD-1⁺ and CD8⁺PD-L1⁺ circulating T cell percentages and were independently associated with poorer PFS (p < 0.00001) and OS (p < 0.00001). Pre-therapy sEV could be useful as non-invasive biomarkers of response to therapy and clinical outcome in NSCLC.

SUBMITTER: Vetsika EK

PROVIDER: S-EPMC8122966 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNon-small cell lung cancer (NSCLC) has a high mortality rate and poor prognosis. The early detection of high-risk patients is essential to improve patient prognosis. Thus, the identification of a non-invasive, non-radiative, convenient, and fast diagnostic approach should be a top priority in NSCLC research. Circulating extracellular RNAs (exRNAs) in the plasma are potential biomarkers for NSCLC.MethodsWe used RNA-sequencing (RNA-seq) technology to explore the NSCLC-related RNAs, especially the circular RNAs (circRNAs). The circRNA-targeted micro RNAs (miRNAs) were predicted using 3 circRNA databases [i.e., the Cancer-Specific CircRNA Database (CSCD), circBank, and Circular RNA Interactome]. The circRNA-miRNA-messenger RNA (mRNA) network was constructed using Cytoscape V3.8.0 (Cytoscape Consortium, San Diego, CA, USA). The expression levels of some differentially expressed genes were validated by a quantitative real-time polymerase chain reaction (qRT-PCR) analysis.ResultsThe results showed that the RNA biotypes of the mitochondrial ribosomal RNAs (mt-rRNAs) and mitochondrial transfer RNAs (mt-tRNAs) were upregulated in the NSCLC plasma. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms of the differentially expressed transcripts of NSCLC included oxidative phosphorylation, proton transmembrane transport, and the response to oxidative stress. Additionally, the qRT-PCR validation indicated that hsa_circ_0000722 had significantly higher expression in the NSCLC plasma than the control plasma, but hsa_circ_0006156 did not differ between the NSCLC plasma and the control plasma. The expression levels of miR-324-5p and miR-326 were higher in the NSCLC plasma than the control plasma.ConclusionsIn this study, an exRNA-sequencing strategy was used to identify the expression of NSCLC-specific transcription factors in clinical plasma samples, and hsa_circ_0000722 and hsa-miR-324-5p were identified as potential biomarkers in NSCLC.

Project description:Purpose: Smoking is a strong relative risk factor for lung cancer. Extracellular vesicles (EVs), particularly exosomes, have been implicated in cancers. In this study, we characterized smoking induced extracellular vesicles in smokers with non-small cell lung cancer (NSCLC). Methods: EVs were isolated from bronchoalveolar lavage (BAL) from smokers and NSCLC patients. EV microRNAs (miRNAs) were analyzed by using a TaqMan microRNA assays. Vesicle mRNAs and long non-coding RNAs (lncRNAs) were measured with quantitative RT-PCR. Tumor associated antigens were examined by Western Blot. Results: Higher levels of local site EVs are found in the lung of smokers and NSCLC patients. Further, over 90% of lung EVs are round vesicles of approximately 50-200 nm, ie., exosomes. There are 21 EV miRNAs up regulated, while 10 miRNAs under regulated, in smokers when compared to controls (relative fold > 2, p < 0.05). These miRNAs were further observed to be dysregulated in NSCLC patients when compared to smokers. Bioinformatic analysis demonstrated that Proteoglycans, Fatty acid biosynthesis, ErbB, Hippo, TGF-beta, Wnt, Rap1, AMPK and Ras pathways were the most prominent pathways enriched in NSCLC EV miRNA signatures. In addition, messenger RNA transcripts including EGFR, KRAS, ALK, MET, LKB1, BRAF, PIK3CA, RET, and ROS1 were significantly higher expressed in lung EVs in smokers and NSCLC patients compared to controls. Long non-coding RNAs, including MALAT1, HOTAIR, HOTTIP, AGAP2-AS1, ATB, TCF7, FOXD2-AS1, HOXA11-AS, PCAF1, and BCAR4, were over expressed in EVs from smokers and NSCLC patients. Furthermore, protein levels of tumor associated antigens including BAGE, PD-L1, MAGE-3, and AKAP4 were significantly dysregulated in EVs of smokers and NSCLC patients compared to healthy controls. Conclusions: In conclusion, these data demonstrated an intrinsic relationship of smoking dysregulated EVs and EVs contained RNA, proteins which may involve in the development of NSCLC.

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Small Extracellular Vesicles in Pre-Therapy Plasma Predict Clinical Outcome in Non-Small-Cell Lung Cancer Patients.

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