Comprehensive molecular analyses of a TNF family-based signature with regard to prognosis, immune features, and biomarkers for immunotherapy in lung adenocarcinoma

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.

Immunogenomic Gene Signature of Cell-Death Associated Genes with Prognostic Implications in Lung Cancer

“…In the literature, there are several gene expression-based biomarkers which can stratify patients at high-risk which can be benefited from personalized therapy, but their accuracy and predictive potential remain limited [ 39 , 40 , 41 ]. However, most of these studies are the differential analysis of genomic or transcriptomics features which lack focus on biological pathways [ 22 ]. In this study, we explored the RNA-Seq data of LUAD patients for variations in cell death specific gene expression and its association with immune cells.…”

“…The advancement of multi-omic analysis and differential expression profiles have identified new prognostic biomarkers for LUAD patients [ 21 , 22 ]. Most of these bioinformatics studies are mathematical analyses of whole-scale genetic or transcriptomic data which lack specialized focus on biological pathways [ 22 ]. In this study, LUAD patients were stratified based on cell death-based gene signatures along with the characterization of their immune response.…”

A Novel Prognostic Model of Early-Stage Lung Adenocarcinoma Integrating Methylation and Immune Biomarkers

“… Li et al (2019) revealed that methylation-driver mRNA and lncRNA contributed to the survival of LUAD, and eight mRNAs and four lncRNAs might be candidate biomarkers. Focused on immunity, Zhang et al (2020) constructed the first TNF family-based model for predicting outcomes of LUAD patients, Li et al (2017) developed and validated an individualized immune prognostic signature in early-stage non-squamous NSCLC. However, unavoidable deficiencies existed in previous studies.…”

“…The outcome of tumor development, as well as the responsiveness to cancer immunotherapy, can be influenced by the total number of T cells found within a tumor. Hence, several immune-related prognostic models have been developed ( Li et al, 2017 ; Zhang et al, 2020 ). In short, previous prognostic models of LUAD only focused on a single biological factor.…”

Do mRNA profiles of lung adenocarcinomas provide information that will help individual patients?

“…In this article of EBioMedicine, Zhang et al try to advance this effort by showing that a five-gene (TNFRSF -6B, 13C, 14, 1A, 27/ EDA2R) tumour necrosis factor (TNF) family tumour transcriptomic signature can stratify patients with lung adenocarcinoma (LUAD) into distinct prognostic cohorts [2]. Importantly, they also find these TNF family gene expression profiles associate with distinct tumour microenvironment (TME) immune cell composition.…”