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Dissecting the ferroptosis-related prognostic biomarker and immune microenvironment of driver gene-negative lung
Rui Zhou1, Hao-Chuan Ma1, Yi-Hong Liu2
1The Second Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
Abstract:
Despite significant advances in targeted and immune therapy for non-small cell lung cancer (NSCLC), effective therapies for wild-type epidermal growth factor receptor/anaplastic lymphoma kinase (EGFR/ALKWT) with low expression of programmed death ligand-1 (PD-L1) NSCLC remain elusive. Numerous studies have shown that ferroptosis plays an essential role in antitumor activity. To identify the molecular regulation patterns associated with ferroptosis, 351 EGFR/ALKWT NSCLC samples with low-level PD-L1 were extracted from The Cancer Genome Atlas (TCGA) and clustered using the k-means clustering technique. The two clusters associated with ferroptosis showed significantly different prognoses. In total, 169 differential expression genes (DEGs) were identified. Cluster differential analysis revealed that Cluster 1 had a significantly poorer overall survival (OS) and was associated with more negative immune regulation. In addition, TCGA samples were randomly assigned in a 7:3 ratio to a training group or testing group. A signature of eight genes associated with ferroptosis was established in the training cohort using DEGs and validated in the test cohort and three independent cohorts (GSE72049, GSE41271, and GSE50081). The 5-year area under the curve (AUC) was 0.713, which was significantly higher than that of other predictors, including TNM stage and age. Furthermore, the risk score was associated with immune function, immune infiltration, and immunotherapy response, with high-risk patients having a worse prognosis, an immune-suppressing phenotype, and a poor response to immune checkpoint inhibitors. This study aims to contribute to our understanding of the biological role of ferroptosis in EGFR/ALKWT NSCLC with low-level PD-L1, laying the groundwork for the development of novel therapeutic strategies.
Insights
Ferroptosis plays a key role in non-small cell lung cancer (NSCLC) with wild-type EGFR/ALK and low PD-L1. A novel eight-gene ferroptosis signature predicts prognosis and immunotherapy response in these NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Targeted and immune therapies show limitations for non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor/anaplastic lymphoma kinase (EGFR/ALKWT) and low programmed death ligand-1 (PD-L1) expression.
- Ferroptosis, a regulated form of cell death, has emerged as a critical factor in antitumor activity.
- Understanding the molecular mechanisms of ferroptosis in this specific NSCLC subtype is crucial for developing new treatments.
Purpose of the Study:
- To identify molecular regulation patterns associated with ferroptosis in EGFR/ALKWT NSCLC with low PD-L1.
- To develop a ferroptosis-based gene signature for predicting prognosis and immunotherapy response.
- To explore the role of ferroptosis in immune regulation within this NSCLC subgroup.
Main Methods:
- Utilized k-means clustering on 351 EGFR/ALKWT NSCLC samples from The Cancer Genome Atlas (TCGA) with low PD-L1.
- Identified 169 differentially expressed genes (DEGs) and established an eight-gene ferroptosis signature.
- Validated the signature in independent cohorts and assessed its association with clinical outcomes, immune function, and immunotherapy response.
Main Results:
- Two ferroptosis-associated clusters exhibited significantly different prognoses, with one cluster showing poorer overall survival (OS) and negative immune regulation.
- The developed eight-gene ferroptosis signature demonstrated strong predictive power (5-year AUC of 0.713), outperforming TNM stage and age.
- High-risk scores correlated with worse prognosis, an immune-suppressing phenotype, and poor response to immune checkpoint inhibitors.
Conclusions:
- Ferroptosis plays a significant role in the biological behavior of EGFR/ALKWT NSCLC with low PD-L1.
- The novel eight-gene signature serves as a robust predictor of prognosis and immunotherapy response in this patient population.
- These findings provide a foundation for novel therapeutic strategies targeting ferroptosis in NSCLC.
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