Integrated Single-Cell Lung Cancer Atlas Revealed Distinct Fibroblast Phenotypes between Adenocarcinoma and Squamous Cell Carcinomas

The tumor microenvironment (TME) not only influences cancer progression but has also been shown to have a significant impact on patient prognosis. One of the major TME components is cancer-associated fibroblasts (CAFs), of which several subtypes are identified in tumor tissues. Although scRNA-seq technology is a powerful tool to investigate the cellular proportion and composition in tissues, large-scale datasets are required to analyze a small number of cell populations. Here, we constructed an integrated single-cell RNA-seq dataset for non-small cell lung cancer (NSCLC) by compiling publicly-available data and demonstrated differences in TME heterogeneity and cellular composition between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Particularly, we identified significant differences in CAF subtypes between LUAD and LUSC. Inflammatory CAFs (iCAFs) were dominantly found in LUAD, while myofibroblastic CAFs (mCAFs) were more common in LUSC. Co-culture analysis with lung fibroblasts confirmed that LUAD cells induced iCAF phenotype and, in contrast, LUSC promoted myofibroblastic differentiation. Correlation analysis with patient prognosis identified mCAF as a poor prognostic factor in both LUAD and LUSC, but iCAF was found to be a poor prognostic factor only in LUSC, and vice versa in LUAD. This work highlights important considerations on CAF subtype dominance in LUAD and LUSC, which may relate to patient prognosis.