A translational study on the survival and molecular mechanism of PD-L1 expression in EGFR-mutant NSCLC treated with osimertinib

Highly expressed programmed death-ligand 1 (PD-L1) has been associated with poor clinical outcomes in patients with epidermal growth factor receptor (<i>EGFR</i>)-mutated non-small cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs). However, the prognostic significance of PD-L1 expression in the context of first-line osimertinib treatment remains unclear. In this retrospective study, we analyzed 317 patients with <i>EGFR</i>-mutated stage III-IV lung adenocarcinoma treated with first-line osimertinib. Patients with high PD-L1 expression demonstrated significantly shorter progression-free survival and overall survival compared to those with low PD-L1 expression. Transcriptomic analysis revealed upregulation of interferon-gamma (IFN-γ) and interleukin (IL)-6/JAK/STAT3 pathways in high PD-L1 tumors. Flow cytometry identified an increased proportion of CD56^bright natural killer (NK) cells in patients with high PD-L1 expression. <i>In vitro</i> experiments further demonstrated that IFN-γ induces PD-L1 expression via STAT3 activation. These findings provide evidence that baseline PD-L1 expression may serve as a prognostic biomarker for patients with <i>EGFR</i>-mutated NSCLC receiving first-line osimertinib and implicate the CD56^bright NK cell/IFN-γ/STAT3 axis in the regulation of PD-L1 expression.