Background: The study focuses on PD-L1 expression as an essential biomarker for gauging the response of EGFR/ALK wild-type NSCLC patients to FDA-approved immune checkpoint inhibitors (ICIs). It aims to explore clinical, molecular, and immune microenvironment characteristics associated with PD-L1 expression in EGFR/ALK wild-type lung adenocarcinoma patients eligible for ICI therapy. Methods: In this retrospective study, tumor samples from 359 Chinese EGFR/ALK wild-type lung adenocarcinoma patients underwent comprehensive evaluations for PD-L1 expression and NGS-targeted sequencing. The investigation encompassed the analysis and comparison of clinical traits, gene mutations, pathways, and immune signatures between two groups categorized by PD-L1 status: negative (TPS < 1%) and positive (TPS >= 1%). Additionally, the study explored the link between genomic changes and outcomes following immunotherapy. Results: High tumor mutational burden correlated significantly with PD-L1 positivity in patients with EGFR/ALK wild-type lung adenocarcinoma. Gene alterations, including TP53, KRAS, and others, were more pronounced in the PD-L1 positive group. Pathway analysis highlighted higher frequencies of alterations in pathways like RTK/RAS, p53, and Hippo in PD-L1-positive patients. The Hippo pathway's relevance was confirmed in separate immunotherapy cohorts, associated with better outcomes. In terms of immune cell infiltration, Hippo mutants exhibited higher levels of CD68(+) PD-L1(+) macrophages, CD8(+) T cells, and CD8(+) PD-1(-) T cells. Conclusions: This study offers insights into genomic features of Chinese EGFR/ALK wild-type lung adenocarcinoma patients based on PD-L1 expression. Notably, Hippo pathway alterations were linked to improved immunotherapy outcomes. These findings suggest connections between the Hippo pathway and PD-L1 expression, warranting further clinical and functional investigations. The research advances our understanding of PD-L1 expression's genomic context and immunotherapy response in EGFR/ALK wild-type lung adenocarcinoma.
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