Serum extracellular vesicle microRNAs as potential biomarkers to predict pembrolizumab response and prognosis in metastatic non-small cell lung cancer patients
IntroductionCirculating Extracellular Vesicles (cEVs) could represent new non-invasive biomarkers for diagnosis and prognosis in tumors. In the context of Non-Small Cell Lung Cancer (NSCLC) immunotherapy there’s a great need for novel predictive and prognostic biomarkers. This study aims to analyze...
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Frontiers Media S.A.
2025-06-01
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| author | Daniela Lamorte Luciana De Luca Alfredo Tartarone Stefania Trino Irene Giulivo Angelo De Stradis Maddalena Maietti Antonella Caivano Ilaria Laurenzana |
| author_facet | Daniela Lamorte Luciana De Luca Alfredo Tartarone Stefania Trino Irene Giulivo Angelo De Stradis Maddalena Maietti Antonella Caivano Ilaria Laurenzana |
| author_sort | Daniela Lamorte |
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| description | IntroductionCirculating Extracellular Vesicles (cEVs) could represent new non-invasive biomarkers for diagnosis and prognosis in tumors. In the context of Non-Small Cell Lung Cancer (NSCLC) immunotherapy there’s a great need for novel predictive and prognostic biomarkers. This study aims to analyze cEVs microRNAs in serum of advanced stage NSCLC patients with PD-L1 expression ≥50% at diagnosis, before first-line pembrolizumab, to evaluate their possible role as potential biomarkers for immunotherapy response prediction and outcomes.MethodscEVs were isolated from serum of healthy subjects and NSCLC patients at diagnosis. All patients had tumor PD-L1≥50% and cEVs were extracted before first-line pembrolizumab treatment. cEVs were then characterized for morphology, integrity, concentration, size and protein contaminants. Subsequently, microRNA content (miR-10a, miR-21, miR-22, miR-30a, miR-34a, miR-106b, miR-125b, miR-150, miR-155, miR-181a, miR-181b, miR-451a) was investigated by digital PCR. Additionally, miRNA-targets and their roles were evaluated. All data were associated with immunotherapy response, Progression Free Survival (PFS), Overall Survival (OS), Eastern Cooperative Oncology Group Performance Status (ECOG-PS) and metastases.ResultsTwelve NSCLC-related microRNAs have been found, for the first time, in serum cEVs from a specific cohort of metastatic advanced stage NSCLC patients. Through a functional analysis, these microRNAs are found to be connected to each other and involved in the pathology of NSCLC, particularly in IGF/P53/VEGF/NOTCH/PI3K pathways, in cytokine/interleukin signaling and in the immune system. Specifically, we demonstrated that cEV miR-106b, miR-451a, miR-181 and miR-10a were significantly up-regulated in non-responder patients compared to responder ones (p-value=0.08-0.1) predicting with high accuracy, already at diagnosis, treatment response. Furthermore, a low level of all these microRNAs predicted improved PFS (p-value=0.009-0.02) and a low amount of miR-106b predicted longer OS (p=0.069). In addition, it was observed that high levels of miR-106b and miR-451a are indicative of a high number of metastases (p=0.05/0.04, respectively) and of ECOG-PS=0.DiscussionThis is the first study that investigated specific potential serum cEV miRNAs to predict with high accuracy immunotherapy response and prognosis in specific metastatic NSCLC patients, already at diagnosis. Collectively, our cEV miRNA analysis identifies novel circulating biomarkers that are easily accessible and non-invasive, offering a potential blood-based tool to guide personalized medicine in NSCLC. |
| format | Article |
| id | doaj-art-d99ccf245ad544fb853626530d2daa25 |
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| publishDate | 2025-06-01 |
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| spelling | doaj-art-d99ccf245ad544fb853626530d2daa252025-08-20T02:31:52ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.15409061540906Serum extracellular vesicle microRNAs as potential biomarkers to predict pembrolizumab response and prognosis in metastatic non-small cell lung cancer patientsDaniela Lamorte0Luciana De Luca1Alfredo Tartarone2Stefania Trino3Irene Giulivo4Angelo De Stradis5Maddalena Maietti6Antonella Caivano7Ilaria Laurenzana8Laboratory of Preclinical and Translational Research, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, ItalyUnit of Clinical Pathology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, ItalyDepartment of Onco-Hematology, Division of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, ItalyLaboratory of Preclinical and Translational Research, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, ItalyTrial Office, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, ItalyInstitute for Sustainable Plant Protection, National Research Council (CNR), Bari, ItalyUnit of Clinical Pathology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, ItalyUnit of Clinical Pathology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, ItalyLaboratory of Preclinical and Translational Research, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, ItalyIntroductionCirculating Extracellular Vesicles (cEVs) could represent new non-invasive biomarkers for diagnosis and prognosis in tumors. In the context of Non-Small Cell Lung Cancer (NSCLC) immunotherapy there’s a great need for novel predictive and prognostic biomarkers. This study aims to analyze cEVs microRNAs in serum of advanced stage NSCLC patients with PD-L1 expression ≥50% at diagnosis, before first-line pembrolizumab, to evaluate their possible role as potential biomarkers for immunotherapy response prediction and outcomes.MethodscEVs were isolated from serum of healthy subjects and NSCLC patients at diagnosis. All patients had tumor PD-L1≥50% and cEVs were extracted before first-line pembrolizumab treatment. cEVs were then characterized for morphology, integrity, concentration, size and protein contaminants. Subsequently, microRNA content (miR-10a, miR-21, miR-22, miR-30a, miR-34a, miR-106b, miR-125b, miR-150, miR-155, miR-181a, miR-181b, miR-451a) was investigated by digital PCR. Additionally, miRNA-targets and their roles were evaluated. All data were associated with immunotherapy response, Progression Free Survival (PFS), Overall Survival (OS), Eastern Cooperative Oncology Group Performance Status (ECOG-PS) and metastases.ResultsTwelve NSCLC-related microRNAs have been found, for the first time, in serum cEVs from a specific cohort of metastatic advanced stage NSCLC patients. Through a functional analysis, these microRNAs are found to be connected to each other and involved in the pathology of NSCLC, particularly in IGF/P53/VEGF/NOTCH/PI3K pathways, in cytokine/interleukin signaling and in the immune system. Specifically, we demonstrated that cEV miR-106b, miR-451a, miR-181 and miR-10a were significantly up-regulated in non-responder patients compared to responder ones (p-value=0.08-0.1) predicting with high accuracy, already at diagnosis, treatment response. Furthermore, a low level of all these microRNAs predicted improved PFS (p-value=0.009-0.02) and a low amount of miR-106b predicted longer OS (p=0.069). In addition, it was observed that high levels of miR-106b and miR-451a are indicative of a high number of metastases (p=0.05/0.04, respectively) and of ECOG-PS=0.DiscussionThis is the first study that investigated specific potential serum cEV miRNAs to predict with high accuracy immunotherapy response and prognosis in specific metastatic NSCLC patients, already at diagnosis. Collectively, our cEV miRNA analysis identifies novel circulating biomarkers that are easily accessible and non-invasive, offering a potential blood-based tool to guide personalized medicine in NSCLC.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1540906/fullNSCLCimmunotherapyliquid biopsybiomarkersextracellular vesiclesmicroRNAs |
| spellingShingle | Daniela Lamorte Luciana De Luca Alfredo Tartarone Stefania Trino Irene Giulivo Angelo De Stradis Maddalena Maietti Antonella Caivano Ilaria Laurenzana Serum extracellular vesicle microRNAs as potential biomarkers to predict pembrolizumab response and prognosis in metastatic non-small cell lung cancer patients Frontiers in Immunology NSCLC immunotherapy liquid biopsy biomarkers extracellular vesicles microRNAs |
| title | Serum extracellular vesicle microRNAs as potential biomarkers to predict pembrolizumab response and prognosis in metastatic non-small cell lung cancer patients |
| title_full | Serum extracellular vesicle microRNAs as potential biomarkers to predict pembrolizumab response and prognosis in metastatic non-small cell lung cancer patients |
| title_fullStr | Serum extracellular vesicle microRNAs as potential biomarkers to predict pembrolizumab response and prognosis in metastatic non-small cell lung cancer patients |
| title_full_unstemmed | Serum extracellular vesicle microRNAs as potential biomarkers to predict pembrolizumab response and prognosis in metastatic non-small cell lung cancer patients |
| title_short | Serum extracellular vesicle microRNAs as potential biomarkers to predict pembrolizumab response and prognosis in metastatic non-small cell lung cancer patients |
| title_sort | serum extracellular vesicle micrornas as potential biomarkers to predict pembrolizumab response and prognosis in metastatic non small cell lung cancer patients |
| topic | NSCLC immunotherapy liquid biopsy biomarkers extracellular vesicles microRNAs |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1540906/full |
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