Abstract 7367: Dissecting cellular and molecular alterations in pre-invasive to invasive lung cancer progression at single-cell resolution

Abstract Non-small cell lung cancer (NSCLC) accounts for most cancer-related deaths worldwide, largely due to diagnosis at advanced metastatic stages. Increased implementation of low-dose computed tomography (CT) -guided screening has led to the identification of non-solid lesions or ground-glass opacities (GGOs) that are not visible on plain chest radiography and can harbor very early-stage tumors. Growth of the lesions and/or development of a solid component can indicate more aggressive behavior. Using the low-dose CT reduced lung cancer mortality by 20%, underscoring the need for early detection and intervention. However, the cellular and molecular determinants contributing to the malignant progression of those early preinvasive lesions remain poorly understood. To assess intratumoral heterogeneity and associated dynamic changes in the immune contexture during early lung carcinogenesis, we performed single-cell RNA-seq and Hyperion imaging on surgically resected freshly harvested tissues from 37 patients (matched solid and non-solid components of lesions and adjacent non-involved lungs), representing a spectrum from preneoplasia to invasive disease. Analysis of 300K cells identified cellular, transcriptomic, and metabolic alterations as well as tumor-stroma cross-talk pathways. Specifically, preinvasive to invasive disease progression was associated with significant changes in the immune landscape determined by an increase in exhausted CD4/CD8 T-cells, suppressive T-regs, polymorphonuclear myeloid-derived suppressor cells, and M2-like macrophages; and a decrease in cytotoxic CD8 T-cells, NK cells, and inflammatory cDC2 cells, suggesting that activation of immunosuppressive/anti-inflammatory microenvironment and suppression of immune activation microenvironment may enable tumor progression. Citation Format: Liron Yoffe. Dissecting cellular and molecular alterations in pre-invasive to invasive lung cancer progression at single-cell resolution abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 7367.