A TNF Family-Based Signature Reveals Significantly Different Prognoses and Immunotherapy Response in Patients with Lung Adenocarcinoma

Tumor Necrosis Factor (TNF) family members play important roles in mounting anti-tumor 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 involved an integrative analysis of the gene expression profiles of TNF family members in LUAD and constructed a TNF family-based prognosis signature. 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 immunotherapy response prediction value of the signature were also explored. 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. Importantly, signature high-risk cases were considered appropriate candidates for immunotherapy. Collectively, this was the first, reliable, TNF family-based prognostic model for predicting outcomes and immunotherapy response, which may emerge as a clinically useful tool for better prognostic management and increased precision in the application of immunotherapy for LUAD patients. Funding Statement: This work was supported by the CAMS Innovation Fund for Medical Sciences (2017-I2M-1-005, 2016-I2M-1-001), the National Key R&D Program of China (2016YFC1303201), the National Natural Science Foundation of China (81802299, 81502514), the Fundamental Research Funds for the Central Universities (3332018070), the National Key Basic Research Development Plan (2018YFC1312105). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: This study was approved by the Institutional Review Boards of The First Affiliated Hospital of Zhengzhou University.