PD-L1 Expression in Non-Small Cell Lung Cancer Specimens: Association with Clinicopathological Factors and Molecular Alterations

Immune checkpoint inhibitors (ICI) targeting programmed cell death-1 or its ligand (PD-L1) have improved outcomes in non-small cell lung cancer (NSCLC). High tumor PD-L1 expression, detected by immunohistochemistry (IHC) typically on formalin-fixed paraffin-embedded (FFPE) histological specimens, is linked to better response. Following our previous investigation on PD-L1 in cytological samples, the aim of this study was to further explore the potential impacts of various clinicopathological and molecular factors on PD-L1 expression. Two retrospective NSCLC cohorts of 1131 and 651 specimens, respectively, were investigated for PD-L1 expression (<1%/1-49%/≥50%), sample type, sample site, histological type, and oncogenic driver status. In both cohorts, PD-L1 was positive (≥1%) in 55% of the cases. Adenocarcinomas exhibited lower PD-L1 expression than squamous cell carcinomas (p < 0.0001), while there was no difference between sample types, tumor locations, or between the two cohorts in multivariate analysis (all p ≥ 0.28). Mutational status correlated significantly with PD-L1 expression (p < 0.0001), with the highest expression for KRAS-mutated cases, the lowest for EGFR-mutated, and the KRAS/EGFR wild-type cases in between. There was no difference in PD-L1 levels between different prevalent KRAS mutations (all p ≥ 0.44), while mucinous KRAS-mutated adenocarcinomas exhibited much lower PD-L1 expression than non-mucinous (p < 0.0001). Our data indicate that cytological and histological specimens are comparable for PD-L1 evaluation. Given the impact of KRAS mutations and the mucinous growth pattern on PD-L1 expression, these factors should be further investigated in studies on ICI response.