Abstract
Background: Tumour Necrosis Factor (TNF) family members play important roles in mounting anti-tumour immune responses, and clinical trials targeting these molecules are ongoing. However, the expression patterns and clinical significance of TNF members in lung adenocarcinoma (LUAD) remain unrevealed. This study aimed to explore the gene expression profiles of TNF family members in LUAD and constructed a TNF family-based prognosis signature. Methods: In total, 1300 LUAD cases from seven different cohorts were collected. Samples from The Cancer Genome Atlas (TCGA) were used as the training set, and the RNA data from five Gene Expression Omnibus (GEO) datasets and qPCR data from 102 samples were used for validation. The immune profiles and potential immunotherapy response prediction value of the signature were also explored. Findings: After univariate Cox proportional hazards regression and stepwise multivariable Cox analysis, a TNF family-based signature was constructed in the TCGA dataset that significantly stratified cases into high- and low-risk groups in terms of OS. This signature remained an independent prognostic factor in multivariate analyses. Moreover, the clinical significance of the signature was well validated in different clinical subgroups and independent validation cohorts. Further analysis revealed that signature high-risk patients were characterized by distinctive immune cell proportions and immune-suppressive states. Additionally, signature scores were positively related to multiple immunotherapy biomarkers. Interpretation: This was the first TNF family-based model for predicting outcomes and immune landscapes for patients with LUAD. The capability of this signature for predicting immunotherapy response needs further validation.