1. Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer
- Author
-
Frigola Rissech, Joan, Navarro, Alejandro, Carbonell, Caterina, Callejo, Anna, Iranzo, Patricia, Cedrés, Susana, Martinez-Marti, Alex, Pardo Aranda, Nuria, Saoudi-Gonzalez, Nadia, Martinez, Débora, Jiménez, José, Sansano, Irene, Mancuso, Francesco M., Nuciforo, Paolo, Montuenga, Luis M., Sanchez-Cespedes, Montse, Prat, Aleix, Vivancos, Ana, Felip, Enriqueta, Amat, Ramón, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Frigola J, Carbonell C, Amat R] Thoracic Cancers Translational Genomics Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Navarro A, Callejo A, Iranzo P, Cedrés S, Martinez-Marti A, Pardo N, Saoudi-Gonzalez N] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Jimenez J, Nuciforo P] Molecular Oncology Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Sansano I] Unitat de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Mancuso FM, Vivancos A] Cancer Genomics Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Felip E] Thoracic Cancers Translational Genomics Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
- Subjects
Male ,0301 basic medicine ,Oncology ,Pulmons - Càncer - Prognosi ,Cancer Research ,Lung Neoplasms ,Somatic cell ,medicine.medical_treatment ,Medicaments antineoplàstics - Ús terapèutic ,NSCLC ,B7-H1 Antigen ,immune checkpoint inhibitors ,Transcriptome ,0302 clinical medicine ,Long-term benefit ,Carcinoma, Non-Small-Cell Lung ,Cytotoxic T cell ,Other subheadings::/therapeutic use [Other subheadings] ,Research Articles ,Aged, 80 and over ,Chromosomal alterations burden ,copy number alterations ,biology ,General Medicine ,Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [DISEASES] ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Diagnosis::Prognosis::Treatment Outcome::Progression-Free Survival [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Progression-Free Survival ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,Immunotherapy ,Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS] ,Research Article ,Adult ,PD-L1 ,medicine.medical_specialty ,Cell type ,long‐term benefit ,tumor mutational burden ,DNA Copy Number Variations ,diagnóstico::pronóstico::resultado del tratamiento::supervivencia libre de progresión [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,lcsh:RC254-282 ,03 medical and health sciences ,Immune checkpoint inhibitors ,Immune system ,chromosomal alterations burden ,Internal medicine ,Exome Sequencing ,Biomarkers, Tumor ,Genetics ,medicine ,Humans ,Lung cancer ,Aged ,Otros calificadores::/uso terapéutico [Otros calificadores] ,business.industry ,acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS] ,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 [ENFERMEDADES] ,medicine.disease ,Tumor mutational burden ,030104 developmental biology ,PD‐L1 ,Copy number alterations ,biology.protein ,business ,Pulmons - Càncer - Tractament - Abstract
We molecularly characterized tumors from non‐small cell lung cancer patients, focusing on long‐term responders to immune checkpoint inhibitors and showed that these patients present high tumor mutation burden and low somatic copy number alteration burden. PD‐L1 expression was also enriched in these patients. Finally, we validated our findings by reanalyzing two public datasets., 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.
- Published
- 2020