Cancer-associated fibroblast marker signatures and stromal composition in usual interstitial pneumonia-associated lung adenocarcinoma: an analysis using a proteomic-immunohistochemical approach.

Lung adenocarcinoma (LUAD) associated with usual interstitial pneumonia (UIP) harbours distinct features compared to lung adenocarcinoma without UIP. Therefore, we aimed to characterise the tumour microenvironment of LUAD with UIP by focusing on cancer-associated fibroblasts (CAFs) and stromal composition. Immunohistochemistry was performed on 32 LUAD samples (16 each with and without UIP) to evaluate CAF marker expression and lymphocyte infiltration. Proteomic analysis of laser-microdissected stromal regions and reanalysis of publicly available single-cell RNA sequencing data were subsequently performed. LUAD with UIP had higher levels of podoplanin and collagen triple helix repeat containing 1 (CTHRC1) immunoreactivity, among the CAF markers examined in the fibrous stroma, increased inflammatory cell infiltration, and higher CD8 + and Foxp3 + lymphocyte counts than LUAD without UIP. The proteomic analysis revealed elevated aggrecan (ACAN) and hyaluronan and proteoglycan link protein 1 (HAPLN1) levels in the stroma of LUAD patients with UIP tissues, which was subsequently confirmed by immunohistochemistry. Single-cell RNA sequencing also supported ACAN and HAPLN1 expression in a subset of CAFs based on public data. The tumour microenvironment of LUAD in patients with UIP harbours distinct characteristics, including altered CAF markers and increased inflammatory cell infiltration in stromal components. Novel stromal proteins such as ACAN and HAPLN1 may play a role in the pathogenesis of LUAD with UIP.