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Abstract Lung adenocarcinoma (LUAD) is the most frequently observed subtype found in non-small cell lung cancer (NSCLC). Despite its high prevalence, the molecular and histological heterogeneity in LUAD pose a significant challenge for providing effective patient care and aiming to reduce the high mortality rate. The histopathological classification proposed by WHO in 2015 describes five histologic patterns of lung adenocarcinoma (lepidic, acinar, papillary, micropapillary, and solid), and it has been shown that the existence of high-grade subtypes (micropapillary and solid) is associated with poorer survival outcomes. Nevertheless, the specific cellular and molecular mechanisms responsible for these clinical outcome differences based on distinct histological patterns remain unclear. Here, we conducted single-cell RNA sequencing (scRNA-seq) to unveil insights into the tumor microenvironment (TME) and identify cancer cell biomarkers associated with distinct histological patterns. Our study involved 18 specimens from primary LUAD patients who underwent surgical resection, all of whom were previously untreated. These specimens were classified into three groups: acinar/papillary (A/P), micropapillary (MP), and solid. Remarkably, patients with solid-type tumors showed a notable enrichment of CD8+ T cell exhaustion, alongside a significant abundance of GPNMB-high macrophages in the myeloid compartment. Additionally, macrophages from the solid-type demonstrated cholesterol-efflux activation, particularly in alveolar macrophages. It is well-known that cholesterol efflux-activated macrophages display a tumor-associated macrophage phenotype, contributing to immunosuppression in the TME. In contrast, the A/P group exhibited a higher enrichment of mast cells compared to the solid-type. This suggests that the solid-type tumor landscape is more immunosuppressive than the A/P group. In the context of cancer cells, we identified that A/P cancer cells displayed a well-differentiated pattern with a high alveolar epithelial type II cell (AT2) signature. In contrast, solid-type cancer cells showed poorly differentiated states, coupled with a significant activation of the epithelial-mesenchymal transition (EMT) process. Remarkably, even within A/P patients, those with a small portion of solid patterns in the tumor tissue showed higher clonal complexity compared to patients without any solid pattern. Furthermore, we found that cancer cell plasticity can be regulated by cell-cell interactions in the TME. Collectively, this study unveils the relationship between histological patterns and the TME, encompassing distinct immune responses and molecular characteristics of cancer cells in LUAD. These findings provide valuable insights for potential targeted therapeutic strategies. Citation Format: Ju Sung Lee, Ji Yun Jeong, Mi Jeong Hong, Hyo-Gyoung Kang, Jin Eun Choi, Ju Young Kim, Yoon Ha Choi, Jong Kyoung Kim, Shin Yup Lee. Deciphering histological subtype-associated cellular and molecular characteristics of lung adenocarcinoma using single-cell RNA sequencing and spatial transcriptomics 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 2942.
Lee et al. (Fri,) studied this question.