Identification of a Novel Costimulatory Molecule-Related Signature to Predict Prognostic Risk and Immunotherapy Response in Hepatocellular Carcinoma

Abstract Background Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies with high mortality. Costimulatory molecule genes (CMGs) play significant roles in establishing anti-tumor immune response. This study is aimed to identify a costimulatory molecule-related gene signature (CMS) for the prospective assessment of the immunotherapy and prognosis in HCC. Methods Data were downloaded from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) for bioinformatics analysis. Five costimulatory molecule genes were identified to construct a prognostic risk model according to LASSO and stepwise Cox regression analysis. Then, univariate and multivariate Cox regression analysis revealed that the prognostic signature could accurately evaluate the survival outcomes for HCC as an independent predictor factor. Based on the median risk score, patients were divided into the high- and low-risk groups which exhibited significant differences of clinical outcomes, gene set enrichment, immune cell infiltration and immunotherapy response. Drug sensitivity correlation analysis was conducted through CellMiner Database for targeted chemotherapeutic agents. Results Five prognosis-related CMGs, including CD40LG, TMIGD2, TNFRSF11A, TNFRSF11B and TNFRSF4, were selected to establish a novel signature which was then validated as an independent prognosis prediction in HCC patients. The five-gene signature could stratify patients into high- and low-risk group which had significant difference in several clinical characteristics, including gender, grade, Barcelona Clinic Liver Cancer (BCLC) stages, T, N and M stages. Furthermore, the ROC curve and the calibration curve of a nomogram showed good predictive function for survival risk. According to functional enrichment analysis, CMGs were highly involved in immune-relevant responses and various metabolic processes, which might help explain the underlying molecular mechanisms and guide treatment for HCC patients. We also found that the signature had a positive correlation with the infiltration of immunocytes and tumor immune microenvironment, illustrating that CD4+ T cell and macrophages play important roles in HCC immune responses. Additionally, TMIGD2 was found to has good sensitivity to a variety of anti-tumor drugs, making it a potential target for HCC precise immunotherapy. Conclusion We established and validated a costimulatory molecule gene signature to reliably predict the prognosis, immunotherapy outcomes, and immune cell infiltration for hepatocellular carcinoma.