Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer.

Autor: Frigola J; Thoracic Cancers Translational Genomics Unit, Hebron Institute of Oncology (VHIO), Vall d, Barcelona, Spain., Navarro A; Oncology Department, Vall d'Hebron University Hospital & Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Carbonell C; Thoracic Cancers Translational Genomics Unit, Hebron Institute of Oncology (VHIO), Vall d, Barcelona, Spain., Callejo A; Oncology Department, Vall d'Hebron University Hospital & Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Iranzo P; Oncology Department, Vall d'Hebron University Hospital & Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Cedrés S; Oncology Department, Vall d'Hebron University Hospital & Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Martinez-Marti A; Oncology Department, Vall d'Hebron University Hospital & Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Pardo N; Oncology Department, Vall d'Hebron University Hospital & Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Saoudi-Gonzalez N; Oncology Department, Vall d'Hebron University Hospital & Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Martinez D; Department of Medical Oncology, Hospital Clinic, Barcelona, Spain.; Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Barcelona, Spain., Jimenez J; Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Sansano I; Pathology Unit, Vall d'Hebron University Hospital, Barcelona, Spain., Mancuso FM; Cancer Genomics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Nuciforo P; Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Montuenga LM; Program in Solid Tumors, Center for Applied Medical Research (CIMA), Pamplona, Spain.; Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.; Navarra Health Research Institute (IDISNA), Pamplona, Spain., Sánchez-Cespedes M; Cancer Genetics Group, Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Germans Trias i Pujol, Badalona, Barcelona, Spain., Prat A; Department of Medical Oncology, Hospital Clinic, Barcelona, Spain.; Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Barcelona, Spain., Vivancos A; Cancer Genomics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Felip E; Thoracic Cancers Translational Genomics Unit, Hebron Institute of Oncology (VHIO), Vall d, Barcelona, Spain.; Oncology Department, Vall d'Hebron University Hospital & Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Amat R; Thoracic Cancers Translational Genomics Unit, Hebron Institute of Oncology (VHIO), Vall d, Barcelona, Spain.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2021 Apr; Vol. 15 (4), pp. 887-900. Date of Electronic Publication: 2021 Jan 06.
DOI: 10.1002/1878-0261.12891
Abstrakt: 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.
(© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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