Effect of genomic and transcriptional alterations in first-line chemotherapy on subsequent immunotherapy in non-small cell lung cancer (NSCLC) patients.

Abstract

9614 Background: Recent studies have demonstrated that first-line immunotherapy has better therapeutic response than second-line immunotherapy in NSCLC patients. However, the mechanism behind this observation has not been elucidated. The aim of this study is to investigate the mechanism of unfavorable influence that the first-line chemotherapy exerts on subsequent immunotherapy. Methods: 29 NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene (EGFR, ALK, ROS1, RET, BRAF, C-MET) mutations were enrolled in this study. Paired cancer tissues before and after chemotherapy were collected, and NGS-based WES and mRNA sequencing were performed. Sequencing data were analyzed with R packages and statistics analysis was performed with SPSS 20 software. P ≤ 0.05 was regarded as statistically significant. Results: We found that the total number of SNV/INDEL mutations and the tumor mutational burden (TMB) decreased significantly following chemotherapy. The decrease of mutation burden correlated well with therapeutic response: patients with partial response (PR) exhibited significant decrease while patients with stable disease (SD) or progression of disease (PD) did not. Meanwhile, a sharp decrease in common mutations before and after chemotherapy was observed in PR and PD patients, but not SD patients, suggesting that mutational change reflected the therapeutic response. The change in copy number variations (CNVs) exhibited similar trends and correlation with therapeutic response. Subsequent analysis on mRNA levels revealed a sharp decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant to immunotherapy response. Pathway enrichment analysis showed that the genes with decreased expression mainly represented immune-related signaling pathways or biological processes. Conclusions: Our study revealed a possible mechanism underlying unsatisfactory multiple-line immunotherapy following chemotherapy, and indicated that first-line chemotherapy may influence the tumor microenvironment to exert unfavorable influence on subsequent immunotherapy.