Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer
Joan Frigola, Alejandro Navarro, Caterina Carbonell, Ana Callejo, Patricia Iranzo, Susana Cedrés, Alex Martinez-Marti, Nuria Pardo, Nadia Saoudi-Gonzalez, Debora Martinez, Jose Jimenez, Irene Sansano, Francesco M Mancuso, Paolo Nuciforo, Luis M Montuenga, Montse Sánchez-Cespedes, Aleix Prat, Ana Vivancos, Enriqueta Felip, Ramon Amat
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.
CITATION Mol Oncol. 2020 Dec 20. doi: 10.1002/1878-0261.12891. Online ahead of print.