Abstract 6524: Single-cell transcriptomic analysis reveals immune landscape in the malignant transformation of normal lung to lung adenocarcinoma in genetic murine models

Abstract Background: Our understanding of the initiation and progression of lung precancers is rudimentary, which has impeded advance for lung cancer prevention and interception. Although human specimens are the gold standard to study human cancer biology, lung precancer specimens designated for research are often very limited. Furthermore, human specimens are not amendable for preclinical intervention studies. We sought to establish and characterize human-relevant murine lung precancer models to study evolution of lung precancers and to provide insights for lung cancer interception. Methods: We established two mouse models, KrasG12D (a genetically engineered mouse model with KrasG12D activating mutation) and CITMs (a carcinogen urethane-induced model) in the same 129S4 background. We performed single-cell transcriptome sequencing of lung tissues collected at 5 time points after induction for each model to characterize the dynamics of immune response along with the initiation and progression of lung adenocarcinoma. Results: A total of 82,198 immune cells were analyzed and 23 immune cell subpopulations were identified. The results demonstrated dynamic changes of immune cell compositions and cell states along with the evolution from normal lung to lung precancers, and to lung adenocarcinomas in both models. CD4+ effector T cells, CD4+ regulatory T cells, mucosal associated invariant T cells (MAIT) and macrophages progressively increased during tumor progression, in contrast to progressively decreasing naive CD4+ T cells, naive CD8+ T cells and naive B cells. In contrast to CITMs, KrasG12D model harbors a clear decrease in conventional dendritic cells (cDCs) and activated B cells, but significantly more neutrophils (Wilcoxon test, P < 0.01). Conclusion: These data provide a temporal atlas of lung cancer evolution during early lung carcinogenesis and a resource for interception preclinical study. Our results revealed progressive immunosuppression along with progression of lung precancers in both genetic and carcinogen-induced models, but the immune features underlying immunosuppression may be different. Citation Format: Hong Chen, Bo Zhu, Junya Fujimoto, Yanhua Tian, Jian-Rong Li, Pingjun Chen, Alexandre Reuben, Monique B. Nilsson, Xiuning Le, Alissa Poteete, Shawna M. Hubert, Don L. Gibbons, Ignacio I. Wistuba, Jia Wu, Chao Cheng, John V. Heymach, Jianjun Zhang. Single-cell transcriptomic analysis reveals immune landscape in the malignant transformation of normal lung to lung adenocarcinoma in genetic murine models [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 6524.