AUTHOR=Signorelli Diego , Ghidotti Patrizia , Proto Claudia , Brambilla Marta , De Toma Alessandro , Ferrara Roberto , Galli Giulia , Ganzinelli Monica , Lo Russo Giuseppe , Prelaj Arsela , Occhipinti Mario , Viscardi Giuseppe , Capizzuto Valentina , Pontis Francesca , Petraroia Ilaria , Ferretti Anna Maria , Colombo Mario Paolo , Torri Valter , Sozzi Gabriella , Garassino Marina Chiara , Jachetti Elena , Fortunato Orazio TITLE=Circulating CD81-expressing extracellular vesicles as biomarkers of response for immune-checkpoint inhibitors in advanced NSCLC JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.987639 DOI=10.3389/fimmu.2022.987639 ISSN=1664-3224 ABSTRACT=

PD-L1 in tumor cells is the only used biomarker for anti PD1/PD-L1 immune-checkpoints inhibitors (ICI) in Non Small Cell Lung Cancer (NSCLC) patients. However, this parameter is inaccurate to predict response, especially in patients with low tumor PD-L1. Here, we evaluated circulating EVs as possible biomarkers for ICI in advanced NSCLC patients with low tumoral PD-L1. EVs were isolated from plasma of 64 PD-L1 low, ICI-treated NSCLC patients, classified either as responders (R; complete or partial response by RECIST 1.1) or non-responders (NR). EVs were characterized following MISEV guidelines and by flow cytometry. T cells from healthy donors were triggered in vitro using patients’ EVs. Unsupervised statistical approach was applied to correlate EVs’ and patients’ features to clinical response. R-EVs showed higher levels of tetraspanins (CD9, CD81, CD63) than NR-EVs, significantly associated to better overall response rate (ORR). In multivariable analysis CD81-EVs correlated with ORR. Unsupervised analysis revealed a cluster of variables on EVs, including tetraspanins, significantly associated with ORR and improved survival. R-EVs expressed more costimulatory molecules than NR-EVs although both increased T cell proliferation and partially, activation. Tetraspanins levels on EVs could represent promising biomarkers for ICI response in NSCLC.