Development and Validation of a 12-Gene Immune Relevant Prognostic Signature for Lung Adenocarcinoma Through Machine Learning Strategies

Background: Although immunotherapy with checkpoint inhibitors is changing the face of lung adenocarcinoma (LUAD) treatments, only limited patients could benefit from it. Therefore, we aimed to develop an immune-relevant-gene-based signature to predict LUAD patients' prognosis and to characterize their tumor microenvironment thus guiding therapeutic strategy. Methods and Materials: Gene expression data of LUAD patients from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were systematically analyzed. We performed Cox regression and random survival forest algorithm to identify immune-relevant genes with potential prognostic value. A risk score formula was then established by integrating these selected genes and patients were classified into high- and low-risk score group. Differentially expressed genes, infiltration level of immune cells, and several immune-associated molecules were further compared across the two groups. Results: Nine hundred and fifty-four LUAD patients were enrolled in this study. After implementing the 2-steps machine learning screening methods, 12 immune-relevant genes were finally selected into the risk-score formula and the patients in high-risk group had significantly worse overall survival (HR = 10.6, 95%CI = 3.21-34.95, P < 0.001). We also found the distinct immune infiltration patterns in the two groups that several immune cells like cytotoxic cells and immune checkpoint molecules were significantly enriched and upregulated in patients from the high-risk group. These findings were further validated in two independent LUAD cohorts. Conclusion: Our risk score formula could serve as a powerful and accurate tool for predicting survival of LUAD patients and may facilitate clinicians to choose the optimal therapeutic regimen more precisely.