Machine Learning for Building Immune Genetic Model in Hepatocellular Carcinoma Patients

Hepatocellular carcinoma (HCC) is the leading liver cancer with special immune microenvironment, which played vital roles in tumor relapse and poor drug responses. In this study, we aimed to explore the prognostic immune signatures in HCC and tried to construct an immune-risk model for patient evaluation.

RNA sequencing profiles of HCC patients were collected from the cancer genome Atlas (TCGA), international cancer genome consortium (ICGC), and gene expression omnibus (GEO) databases (GSE14520). Differentially expressed immune genes, derived from ImmPort database and MSigDB signaling pathway lists, between tumor and normal tissues were analyzed with Limma package in R environment. Univariate Cox regression was performed to find survival-related immune genes in TCGA dataset, and in further random forest algorithm analysis, significantly changed immune genes were used to generate a multivariate Cox model to calculate the corresponding immune-risk score. The model was examined in the other two datasets with recipient operation curve (ROC) and survival analysis. Risk effects of immune-risk score and clinical characteristics of patients were individually evaluated, and significant factors were then used to generate a nomogram.

There were 52 downregulated and 259 upregulated immune genes between tumor and relatively normal tissues, and the final immune-risk model (based on SPP1, BRD8, NDRG1, KITLG, HSPA4, TRAF3, ITGAV and MAP4K2) can better differentiate patients into high and low immune-risk subpopulations, in which high score patients showed worse outcomes after resection (p < 0.05). The differentially enriched pathways between the two groups were mainly about cell proliferation and cytokine production, and calculated immune-risk score was also highly correlated with immune infiltration levels. The nomogram, constructed with immune-risk score and tumor stages, showed high accuracy and clinical benefits in prediction of 1-, 3- and 5-year overall survival, which is useful in clinical practice.

The immune-risk model, based on expression of SPP1, BRD8, NDRG1, KITLG, HSPA4, TRAF3, ITGAV, and MAP4K2, can better differentiate patients into high and low immune-risk groups. Combined nomogram, using immune-risk score and tumor stages, could make accurate prediction of 1-, 3- and 5-year survival in HCC patients.