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Article

Large-Scale Profiling of Extracellular Vesicles Identified miR-625-5p as a Novel Biomarker of Immunotherapy Response in Advanced Non-Small-Cell Lung Cancer Patients

1
Medical Oncology Department, Campus Bio-Medico University of Rome, 00128 Rome, Italy
2
Pathology Department, Campus Bio-Medico University, 00128 Rome, Italy
3
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
4
Department of Molecular Life Sciences and Swiss Institute of Bioinformatics, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
5
Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
6
Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
7
Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
8
Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
9
UOC of Oncology-ASL Latina-Distretto 1, University of Rome “Sapienza”, 04011 Aprilia, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Niels Reinmuth
Cancers 2022, 14(10), 2435; https://doi.org/10.3390/cancers14102435
Received: 12 April 2022 / Revised: 9 May 2022 / Accepted: 12 May 2022 / Published: 14 May 2022
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC) leading to substantial improvement in survival time and quality of life. Nevertheless, the clinical benefit of treatment is still limited to a minority of patients, reflecting the need to identify novel noninvasive biomarkers to improve patient selection. Currently available markers such as PD-L1 expression have important limitations. In this study, we focused on extracellular vesicles (EV)-associated miRNAs produced by cancer cells and their microenvironment that can be easily detected in blood. In particular, after a large-scale screening of 799 EV-miRNAs, we identified EV-miR-625-5p as a novel independent biomarker of response and survival in ICI-treated NSCLC patients, in particular in patients with PD-L1 expression ≥ 50%. EV-miR-625-5p integrated with PDL-1 test could allow the clinician to identify in advance patients that would benefit from ICIs.
Immune checkpoint inhibitors (ICIs) are largely used in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). Novel biomarkers that provide biological information that could be useful for clinical management are needed. In this respect, extracellular vesicles (EV)-associated microRNAs (miRNAs) that are the principal vehicle of intercellular communication may be important sources of biomarkers. We analyzed the levels of 799 EV-miRNAs in the pretreatment plasma of 88 advanced NSCLC patients who received anti-PD-1 therapy as single agent. After data normalization, we used a two-step approach to identify candidate biomarkers associated to both objective response (OR) by RECIST and longer overall survival (OS). Univariate and multivariate analyses including known clinicopathologic variables and new findings were performed. In our cohort, 24/88 (27.3%) patients showed OR by RECIST. Median OS in the whole cohort was 11.5 months. In total, 196 EV-miRNAs out 799 were selected as expressed above background. After multiplicity adjustment, abundance of EV-miR-625-5p was found to be correlated with PD-L1 expression and significantly associated to OR by RECIST (p = 0.0366) and OS (p = 0.0031). In multivariate analysis, PD-L1 staining and EV-miR-625-5p levels were constantly associated to OR and OS. Finally, we showed that EV-miR-625-5p levels could discriminate patients with longer survival, in particular in the class expressing PD-L1 ≥50%. EV-miRNAs represent a source of relevant biomarkers. EV-miR-625-5p is an independent biomarker of response and survival in ICI-treated NSCLC patients, in particular in patients with PD-L1 expression ≥50%. View Full-Text
Keywords: immune checkpoint inhibitors; non-small-cell lung cancer; extracellular vesicles; microRNAs immune checkpoint inhibitors; non-small-cell lung cancer; extracellular vesicles; microRNAs
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MDPI and ACS Style

Pantano, F.; Zalfa, F.; Iuliani, M.; Simonetti, S.; Manca, P.; Napolitano, A.; Tiberi, S.; Russano, M.; Citarella, F.; Foderaro, S.; Vulpis, E.; Zingoni, A.; Masuelli, L.; Bei, R.; Ribelli, G.; Del Re, M.; Danesi, R.; Vincenzi, B.; Perrone, G.; Tonini, G.; Santini, D. Large-Scale Profiling of Extracellular Vesicles Identified miR-625-5p as a Novel Biomarker of Immunotherapy Response in Advanced Non-Small-Cell Lung Cancer Patients. Cancers 2022, 14, 2435. https://doi.org/10.3390/cancers14102435

AMA Style

Pantano F, Zalfa F, Iuliani M, Simonetti S, Manca P, Napolitano A, Tiberi S, Russano M, Citarella F, Foderaro S, Vulpis E, Zingoni A, Masuelli L, Bei R, Ribelli G, Del Re M, Danesi R, Vincenzi B, Perrone G, Tonini G, Santini D. Large-Scale Profiling of Extracellular Vesicles Identified miR-625-5p as a Novel Biomarker of Immunotherapy Response in Advanced Non-Small-Cell Lung Cancer Patients. Cancers. 2022; 14(10):2435. https://doi.org/10.3390/cancers14102435

Chicago/Turabian Style

Pantano, Francesco, Francesca Zalfa, Michele Iuliani, Sonia Simonetti, Paolo Manca, Andrea Napolitano, Simone Tiberi, Marco Russano, Fabrizio Citarella, Simone Foderaro, Elisabetta Vulpis, Alessandra Zingoni, Laura Masuelli, Roberto Bei, Giulia Ribelli, Marzia Del Re, Romano Danesi, Bruno Vincenzi, Giuseppe Perrone, Giuseppe Tonini, and Daniele Santini. 2022. "Large-Scale Profiling of Extracellular Vesicles Identified miR-625-5p as a Novel Biomarker of Immunotherapy Response in Advanced Non-Small-Cell Lung Cancer Patients" Cancers 14, no. 10: 2435. https://doi.org/10.3390/cancers14102435

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