Mutation mapping of PD-L1 expression in advanced non-small cell lung cancer: A real-world retrospective cohort study

Abstract Background : The duration of response to immune checkpoint inhibitors (ICIs) varies because of tumor immune heterogeneity and employing programmed death receptor ligand 1 (PD-L1) expression to evaluate the efficacy of anti-programmed cell death-1 (PD-1)/PD-L1 antibodies remains controversial. Experimental Design : A total of 138 advanced non-small cell lung cancer (NSCLC) patients subdivided into 2 groups - 52 patients with a PD-L1 Expression≥50% and 86 patients with a PD-L1 Expression <50% - based on next-generation sequencing (NGS) to analyze multiple-dimensional data types, including tumor mutation burden (TMB), gene alterations, gene enrichment analysis, therapy response, and immune-related adverse events (irAEs). Results : High level of PD-L1 expression was significantly associated with advanced age and TMB status. The PD-L1≥50% cohort bear mutations of KRAS, NOTCH1, and FAT, while PD-L1<50% group exhibited mutations of EGFR, PTEN, or LATS1/2. Except the ascertained DNA damage response regulation, it seemed that Hippo-YAP signal played a potential role in mediating PD-L1 expression. Even though there was no significant difference between PD-L1≥50% and PD-L1<50% cohorts on therapy response, patients with a PD-L1 Expression≥50% eclicited high irAEs incidence rate and increased plasma interleukin 6 (IL-6) concentration. Conclusions : This real-world retrospective study suggested that high expression of PD-L1 exhibited dysfunction of Hippo signaling and collaborated with anti- cytokines and chemokines therapy may optimize clinical therapy efficacy.