LAUSR

To depict the genomic and immune landscapes of lung adenocarcinomas (ADCs) in ever and never-smokers and guide the design of immunotherapy strategies, we applied multiple deconvolution methods that allow the identification of immune cell infiltration and immune pathway enrichment using a whole exome and transcriptome sequencing-based approach in 145 patient-matched lung ADC and non-malignant lung parenchymal tissue pairs from ever and never smokers in our in-house cohort. Results were subsequently validated by an external lung ADC cohort, including 108 never-smokers and 61 ever-smokers. Firstly, we showed that ever-smokers had an increased abundance of neutrophils and macrophage infiltration, an elevated antigen processing and presentation capacity, and activated T-cell-mediated immunity. Secondly, ever-smokers revealed elevated macrophages in acinar ADCs, decreased mast cells in lepidic ADCs, and increased neutrophils in papillary ADCs, suggesting the tumor-driven immune characteristic discrepancies among various pathologic subtypes of ADC. Thirdly, we identified mutational disparities in tumor mutation burdens, subclonal single nucleotide variants, and the predicted and expressed neoantigens between ever and never-smokers. The mutant gene KRAS preferably occurred in ever-smokers, further contributing to the infiltration of macrophages and expression of cytokines. The copy number variations of immune-related genes (NFIB, TNFAIP3) were identified as conferring to the dysregulated immune environment in ever-smokers. Moreover, a higher genomic instability index was observed in ever-smokers (p = 0.008). Fourthly, the neoantigen was significantly increased in ever-smoker lung ADCs without nodal disease. While DNA immunoediting preferably occurred in never-smokers. Notably, in lung ADC patients with nodal disease, ever-smokers exhibited slightly more homogenous mutations (p = 0.094), consistent with the evolutionary bottleneck during cancer progression. Finally, the lower immunoediting and higher microenvironment scores significantly determined the more prolonged progression-free survival in never-smokers (p < 0.050). Our multiscale genomic and immune profiling analyses thus offer valuable knowledge of tumor-driven immune disparity arising from smoking and provide a robust solution to the rational design of immune therapies. Citation Format: Xiaozheng Kang, Xin Wang, Liyan Ji, Bingfa Yan, Xuan Gao, Xuefeng Xia, Xingsheng Hu. Heterogeneous tumor-driven immune landscapes between lung adenocarcinomas in ever and never-smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2494.