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

• Published in: Cancer science Vol. 110; no. 8; pp. 2348 - 2356
• Main Authors: Chen, Hao, Chong, Wei, Teng, Changcai, Yao, Yueliang, Wang, Xin, Li, Xue
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2019; John Wiley and Sons Inc
• Subjects: Adult; Aged; Aged, 80 and over; APOBEC signature; Apolipoprotein B; Apoptosis; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; Biomarkers, Tumor - genetics; Biomarkers, Tumor - immunology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Female; Gene expression; Generalized linear models; Genomes; Genomics; Humans; Immune checkpoint; immune checkpoint blockade; Immunity - genetics; Immunity - immunology; Immunologic Memory - genetics; Immunological memory; Immunoregulation; Immunotherapy; Infiltration; Killer Cells, Natural - immunology; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lymphocytes; Lymphocytes T; Male; Medical prognosis; Memory cells; Metastases; Middle Aged; Mismatch repair; mRNA; Mutation; Mutation - genetics; Mutation - immunology; Natural killer cells; neoantigen burden; Neoantigens; Non-small cell lung carcinoma; non‐small‐cell lung cancer; Original; Patients; PD-L1 protein; Progression-Free Survival; Proteins; PTEN protein; Regression analysis; RNA editing; Smoking; Statistical analysis; Survival analysis; T-Lymphocytes, Regulatory - immunology; Tumor Burden - genetics; Tumor Burden - immunology; tumor mutation burden; APOBEC signature; tumor mutation burden; neoantigen burden; immune checkpoint blockade; non-small-cell lung cancer
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14113

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 TMB with APOBEC signature preferably predict immunotherapy responders in NSCLC cohort. The CIBERSORT algorithm revealed that high APOBEC mutational activity samples were associated with increased infiltration of CD4 memory activated T cells, CD8+ T cells and natural killer (NK) cells, but reduced infiltration of regulatory T cells. Besides, individual genes mutation of IFNGR1 or VTCN1 were only found in responders; however, the 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 NSCLC. Multivariate analysis of APOBEC mutational signature is strongly associated with objective immune response and progression‐free survival in immunotherapy, but not identified in conventional chemotherapy of the Cancer Genome Atlas (TCGA) samples, suggesting the specific predictive effects of ICB treatment. High APOBEC mutational activity samples were enriched for immune checkpoint gene markers and tumor immune lymphocyte infiltration makers. Combined TMB with an APOBEC signature may preferably predict NSCLC immunotherapy responders. Individual genes mutation of IFNGR1 or VTCN1 were only found in responders; however, PTEN was only noticed in non‐responders.