Abstract
BackgroundIncreasing bodies of evidence reveal that targeting a programmed cell death protein 1 (PD-1) monoclonal antibody is a promising immunotherapy for lung adenocarcinoma. Although PD receptor ligand 1 (PDL1) expression is widely recognized as the most powerful predictive biomarker for anti-PD-1 therapy, its regulatory mechanisms in lung adenocarcinoma remain unclear. Therefore, we conducted this study to explore differentially expressed genes (DEGs) and elucidate the regulatory mechanism of PDL1 in lung adenocarcinoma.MethodsThe GSE99995 data set was obtained from the Gene Expression Omnibus (GEO) database. Patients with and without PDL1 expression were divided into PDL1-positive and PDL1-negative groups, respectively. DEGs were screened using R. The Gene Ontology (GO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed using the Database for Annotation, Visualization and Integrated Discovery. Protein–protein interaction (PPI) networks of DEGs was visualized using Cytoscape, and the MNC algorithm was applied to screen hub genes. A survival analysis involving Gene Expression Profiling Interactive Analysis was used to verify the GEO results. Mutation characteristics of the hub genes were further analyzed in a combined study of five datasets in The Cancer Genome Atlas (TCGA) database.ResultsIn total, 869 DEGs were identified, 387 in the PDL1-positive group and 482 in the PDL1-negative group. GO and KEGG analysis results of the PDL1-positive group mainly exhibited enrichment of biological processes and pathways related to cell adhesion and the peroxisome proliferators-activated receptors (PPAR) signaling pathway, whereas biological process and pathways associated with cell division and repair were mainly enriched in the PDL1-negative group. The top 10 hub genes were screened during the PPI network analysis. Notably, survival analysis revealed BRCA1, mainly involved in cell cycle and DNA damage responses, to be a novel prognostic indicator in lung adenocarcinoma. Moreover, the prognosis of patients with different forms of lung adenocarcinoma was associated with differences in mutations and pathways in potential hub genes.ConclusionsPDL1-positive lung adenocarcinoma and PDL1-negative lung adenocarcinoma might be different subtypes of lung adenocarcinoma. The hub genes might play an important role in PDL1 regulatory pathways. Further studies on hub genes are warranted to reveal new mechanisms underlying the regulation of PDL1 expression. These results are crucial for understanding and applying precision immunotherapy for lung adenocarcinoma.
Highlights
Non–small-cell lung cancer (NSCLC) is a leading malignancy threatening human life and health worldwide (Herbst, Morgensztern & Boshoff, 2018; Zhang et al, 2019)
The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment results in the PD receptor ligand 1 (PDL1)-positive group revealed that the enriched pathways were mainly those involved in cell adhesion molecules, peroxisome proliferators-activated receptors (PPAR) signaling, and ECM-receptor interaction
PDL1 expression has been proposed as a predictive biomarker, suggesting that it plays a major role in immune regulation in lung adenocarcinoma
Summary
Non–small-cell lung cancer (NSCLC) is a leading malignancy threatening human life and health worldwide (Herbst, Morgensztern & Boshoff, 2018; Zhang et al, 2019). Patients with >50% PDL1 expression treated using anti-PD-1 therapy showed a longer progression-free survival (PFS) period than did those treated using standard chemotherapy as the first-line treatment for NSCLC. Increasing bodies of evidence reveal that targeting a programmed cell death protein 1 (PD-1) monoclonal antibody is a promising immunotherapy for lung adenocarcinoma. PD receptor ligand 1 (PDL1) expression is widely recognized as the most powerful predictive biomarker for anti-PD-1 therapy, its regulatory mechanisms in lung adenocarcinoma remain unclear. We conducted this study to explore differentially expressed genes (DEGs) and elucidate the regulatory mechanism of PDL1 in lung adenocarcinoma. The prognosis of patients with different forms of lung adenocarcinoma was associated with differences in mutations and pathways in potential hub genes. Further studies on hub genes are warranted to reveal new mechanisms underlying the regulation of PDL1 expression
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