The immune response‐related mutational signatures and driver genes in non‐small‐cell lung cancer

摘要

Immune checkpoint blockade (ICB) therapy has achieved remarkable clinical benefit in non‐small‐cell lung cancer (NSCLC), but our understanding of biomarkers that predict the response to ICB remain obscure. Here we integrated somatic mutational profile and clinicopathologic information from 113 NSCLC patients treated by ICB (CTLA‐4/PD‐1). High tumor mutation burden (TMB) and neoantigen burden were identified significantly associated with improved efficacy in NSCLC immunotherapy. Furthermore, we identified apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like (APOBEC) mutational signature was markedly associated with responding of ICB therapy (log‐rank test, P = .001; odds ratio (OR), 0.18 [95% CI, 0.06‐0.50], P < .001). The association with progression‐free survival remained statistically significant after controlling for age, sex, histological type, smoking, PD‐L1 expression, hypermutation, smoking signature and mismatch repair (MMR) (HR, 0.30 [95% CI, 0.12‐0.75], P = .010). Combined high style="fixed-case">TMB with style="fixed-case">APOBEC signature preferably predict immunotherapy responders in style="fixed-case">NSCLC cohort. The style="fixed-case">CIBERSORT algorithm revealed that high style="fixed-case">APOBEC mutational activity samples were associated with increased infiltration of style="fixed-case">CD4 memory activated T cells, style="fixed-case">CD8⁺ T cells and style="fixed-case">natural killer (NK) cells, but reduced infiltration of regulatory T cells. Besides, individual genes mutation of style="fixed-case">IFNGR1 or style="fixed-case">VTCN1 were only found in responders; however, the style="fixed-case">PTEN mutation was only found in non‐responders (Fisher's exact test, all P < .05). These findings may be applicable for guiding immunotherapy for patients with style="fixed-case">NSCLC.