Lung adenocarcinoma WHO histological classes contain distinct immune cell profiles

Abstract Lung adenocarcinoma (LUAD) is classified internationally into six histological subtypes that predict clinical outcomes. Mutation analyses identify targets but provide less prognostic information than histological appearances. Immunotherapy in LUAD is constrained by the unpredictable immune environment within tumours. We therefore characterised relationships between WHO histological classification, common mutations, and underlying transcriptomic and immune profiles in 89 LUAD cases. Mutation profiles poorly correlated with histology or survival. Global gene expression was structured into 12 modules, identifying different tumour cells and pathways within WHO subtypes. Tumour classes also held distinctive immune cell profiles. Transcripts within high-risk solid tumours indicated enrichment of CD8+ and activated CD4+ T-cells, suggesting responsivity to immunotherapy. Independently from histologic classification, 31 transcripts were strongly associated with survival and were enriched in macrophage and fibroblast derived networks. The results suggest histological subtype stratification and typing for survival-associated markers have the potential to inform clinical trials of LUAD.