Detalle Publicación

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

Autores: Frigola, J.; Navarro, A.; Carbonell, C.; Callejo, A.; Iranzo, P.; Cedres, S.; Martinez-Marti, A.; Pardo, N.; Saoudi-Gonzalez, N.; Martinez, D.; Jimenez, J.; Sansano, I.; Mancuso, FM.; Nuciforo, P.; Montuenga Badía, Luis; Sanchez-Cespedes, M.; Prat, A.; Vivancos, A.; Felip, E. (Autor de correspondencia); Amat, R.
Título de la revista: MOLECULAR ONCOLOGY
ISSN: 1574-7891
Volumen: 15
Número: 4
Páginas: 887 - 900
Fecha de publicación: 2021
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.