The complex interplay of TROP2 and PD-L1 in immune regulation and drug resistance in lung cancer.

The complex interplay of TROP2 and PD-L1 in lung adenocarcinoma (LUAD) influences drug resistance and immunotherapy efficacy remains incompletely understood yet. In this study, we investigated the relationship between TACSTD2 (encoding TROP2) and PD-L1 expression through transcriptome analysis, immunohistochemistry, and single-cell RNA sequencing in lung cancer cell lines, tumor tissues, and immune cells, focusing on PC9 parental and drug-resistant variants. TACSTD2 expression strongly correlated with poor clinical outcomes, particularly in immunotherapy-treated patients (HR 1.71 for OS, 2.95 for PFS). Our transcriptome analysis revealed distinct resistance mechanisms involving MAPK signaling and immune receptor regulation pathways. Immunohistochemistry demonstrated significantly elevated TROP2 expression in tumor tissues compared to normal samples, with notably higher levels in PD-L1 positive specimens. We observed significant negative correlations between TACSTD2 expression and CD8 T cell infiltration (Rho = -0.11, P = 1.44e-02), alongside positive correlations with cancer-associated fibroblasts (Rho = 0.094, P = 3.68e-02). Single-cell RNA sequencing identified two distinct cancer subtypes with differential TACSTD2 expression, while gene ontology analysis highlighted enrichment in cell adhesion and immune interaction pathways. These findings provide novel insights into the molecular mechanisms underlying TROP2 and PD-L1 interactions in LUAD, offering potential new diagnostic markers and therapeutic strategies through improved understanding of tumor microenvironment dynamics and resistance mechanisms.