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Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer Navarro Mendivil, Alejandro Callejo Perez, Ana Iranzo Gómez, Patricia Cedres Perez, Susana Martínez Marti, Alexandre Pardo Aranda, Nuria Jiménez Flores, José Antonio Sansano Valero, Irene Mancuso, Francesco Mattia Nuciforo, Paolo Giovanni Vivancos Prellezo, Ana Amat, Ramon Saoudi Gonzalez, Nadia Carbonell, Caterina Frigola Rissech, Joan Felip Font, Enriqueta Pulmons - Càncer - Tractament Medicaments antineoplàstics - Ús terapèutic Pulmons - Càncer - Prognosi DISEASES::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Diagnosis::Prognosis::Treatment Outcome::Progression-Free Survival CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents Other subheadings::Other subheadings::/therapeutic use ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::diagnóstico::pronóstico::resultado del tratamiento::supervivencia libre de progresión COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos Otros calificadores::Otros calificadores::/uso terapéutico Càrrega d'alteracions cromosòmiques; Inhibidors del punt de control immunitari; Càrrega mutacional del tumor Chromosomal alterations burden; Imune checkpoint inhibitors; Tumor mutational burden Carga de alteraciones cromosómicas; Inhibidores de los puntos de control inmunitarios; Carga mutacional del tumor Immunotherapy has transformed advanced non-small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long-lasting responses in some patients. However, the molecular determinants driving these long-term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long-term immune checkpoint inhibitors (ICIs)-associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long-term responders [>18 months of progression-free survival (PFS)]. We performed whole-exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD-L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long-term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD-L1) expression is increased in patients with benefit, mainly in those with long-term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long-term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD-L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI-treated patients with NSCLC. Thus, our data indicate that TMB is associated with long-term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD-L1 are complementary determinants of response to ICIs. Instituto Carlos III-ISCIII. Grant Number: FIS PI17/00938. Fundacion Cientifica Asociación Española Contra el Cancer. Grant Number: GCB14142170. Catalan Government/AGAUR. Grant Number: 2017 – SGR – 1738 2021-12-01T13:17:30Z 2021-12-01T13:17:30Z 2021-04 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Molecular Oncology;15(4) https://doi.org/10.1002/1878-0261.12891 info:eu-repo/grantAgreement/ES/PE2013-2016/PI17%2F00938 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Wiley Scientia