Genomic profiles and their associations with TMB, PD-L1 expression, and immune cell infiltration landscapes in synchronous multiple primary lung cancers

• Published in: Journal for immunotherapy of cancer 2021-12, Vol.9 (12), p.e003773
• Main Authors: Hu, Chunhong, Zhao, Lishu, Liu, Wenliang, Fan, Songqing, Liu, Junqi, Liu, Yuxuan, Liu, Xiaohan, Shu, Long, Liu, Xianling, Liu, Ping, Deng, Chao, Qiu, Zhenhua, Chen, Chen, Jiang, Yi, Liang, Qingchun, Yang, Lingling, Shao, Yang, He, Qiongzhi, Yu, Danlei, Zeng, Yue, Li, Yizheng, Pan, Yue, Zhang, Sujuan, Shi, Shenghao, Peng, Yurong, Wu, Fang
• Format: Article
• Language: English
• Subjects: Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - immunology; Adenocarcinoma of Lung - metabolism; Adenocarcinoma of Lung - pathology; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Basic Tumor Immunology; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Correlation analysis; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes; genetic markers; Humans; Immunotherapy; Kinases; Ligands; Lung cancer; lung neoplasms; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lymphocytes; Lymphocytes, Tumor-Infiltrating - immunology; macrophages; Male; Middle Aged; Mutation; Neoplasms, Multiple Primary - genetics; Neoplasms, Multiple Primary - immunology; Neoplasms, Multiple Primary - metabolism; Neoplasms, Multiple Primary - pathology; Patients; Surgery; Tumor Microenvironment; Tumor-Associated Macrophages - immunology; tumor-infiltrating; Tumors
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2021-003773

BackgroundDiagnosing and treating patients with multiple primary lung cancers (MPLCs) bring challenges to the clinic, and the preliminary evidence has revealed unsatisfying outcomes after targeted therapy and immunotherapy. Therefore, we surveyed genomic profiles of MPLCs and their possible associations with tumor mutation burden (TMB), programmed death-ligand 1 (PD-L1), and the immune cell infiltration landscape.Materials and methodsA total of 112 patients with MPLCs with surgically resected 294 tumors were eligible, and 255 tumors were sequenced using a 1021-gene panel. Immunohistochemistry staining was performed to evaluate the levels of PD-L1 and the density of CD3+/CD8+ tumor-infiltrating lymphocytes (TILs), and CD68+/CD163+ tumor-associated macrophages (TAMs) at the central tumor and invasive margin, and immunotypes were generated based on those variables.ResultsMPLCs often occur simultaneously in non-smoker women younger than 60 years and manifest as ground-glass opacities, adenocarcinoma, and stage I lung lesions. The most frequently mutated genes in the 255 tumors were EGFR (56%), ERBB2 (12%), TP53 (12%), BRAF (11%), RBM10 (11%), and KRAS (9%). We found 87 (77.7%) patients with diverse genomic profiles, and 61 (54.5%) who shared at least one putative driver gene between different tumors presented more aggressive tumors. The median TMB was 1.92 mutations/Mb, and high-TMB (≥3) lesions often harbored EGFRL858R/KRASG12C/RBM10/TP53/LRP1B mutations or wild-type ERBB2. Only 8.1% of patients and 3.9% of lesions were positive for PD-L1 on tumor cells, and this positivity was more frequent in LRP1B/TP53-mutant tumors. EGFRL858R/RBM10/TP53 mutations were positively associated with specific immune cells and an inflamed immunotype, but ERBB2 mutations were negatively correlated. TMB, CD3+TILs, and CD68+/CD163+ TAMs presented with significant heterogeneity among paired tumors (all kappa