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

Mol Oncol. 2021 Apr;15(4):887-900. doi: 10.1002/1878-0261.12891. Epub 2021 Jan 6.

Abstract

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.

Keywords: NSCLC; PD-L1; chromosomal alterations burden; copy number alterations; immune checkpoint inhibitors; long-term benefit; tumor mutational burden.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • B7-H1 Antigen / genetics
  • Biomarkers, Tumor / genetics
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • DNA Copy Number Variations
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Immunotherapy
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Male
  • Middle Aged
  • Progression-Free Survival
  • Transcriptome
  • Whole Exome Sequencing

Substances

  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • Immune Checkpoint Inhibitors