Identification of a prognostic and therapeutic immune signature associated with hepatocellular carcinoma

Abstract

Background Hepatocellular carcinoma (HCC) is one of the most prevalent and inflammation-associated cancers. The tumor microenvironment (TME) plays an essential role in HCC development and metastasis, leading to poor prognosis. The overall TME immune cells infiltration characterizations mediated by immune-related genes (IRGs) remain unclear. In this study, we aimed to investigate whether immune-related genes could be indicators for the prognosis of HCC patients and TME cell infiltration characterization as well as responses to immunotherapy. Methods We obtained differentially expressed immune-related genes (DE IRGs) between normal liver tissues and liver cancer tissues from The Cancer Genome Atlas (TCGA) database. To identify the prognostic genes and establish an immune risk signature, we performed univariable Cox regression survival analysis and the Least Absolute Shrinkage and Selector Operation (LASSO) regression based on the DE IRGs by robust rank aggregation method. Cox regression analysis was used to identify independent prognostic factors in HCC. We estimated the immune cell infiltration in TME via CIBERSORT and immunotherapy response through TIDE algorithm. Results We constructed an immune signature and validated its predictive capability. The immune signature included 7 differentially expressed IRGs: BIRC5, CACYBP, NR0B1, RAET1E, S100A8, SPINK5, and SPP1. The univariate and multivariate cox analysis showed that the 7-IRGs signature was a robust independent prognostic factor in the overall survival of HCC patients. The 7-IRG signature was associated with some clinical features, including gender, vascular invasion, histological grade, clinical stage, T stage. We also found that the 7-IRG signature could reflect the infiltration characterization of different immunocytes in the tumor microenvironment (TME) and had a good correlation with immune checkpoint molecules, revealing that the poor prognosis might be partly due to immunosuppressive TME. The Tumour Immune Dysfunction and Exclusion (TIDE) analysis data showed that the 7-IRG signature had great potential for indicating the immunotherapy response in HCC patients. The mutation analysis demonstrated a significant difference in the tumor mutation burden (TMB) between the high- and low-risk groups, partially explaining this signature's predictive value. Conclusion In a word, we constructed and validated a novel, immune-related prognostic signature for HCC patients. This signature could effectively indicate HCC patients' survival and immunotherapy response. And it might act as potential immunotherapeutic targets for HCC patients.

Tumor Mutation Burden-Associated LINC00638/miR-4732-3p/ULBP1 Axis Promotes Immune Escape via PD-L1 in Hepatocellular Carcinoma

“…Unfortunately, however, few clinical studies have revealed the role of TMB in HCC. We and others found a significant correlation between TMB and immune infiltration in HCC ( 5 – 7 ). Most importantly, the PS model was significantly associated with TMB and immune infiltration.…”

“…A detailed understanding of the mechanism underlying immune infiltration may favor precision immunotherapy in HCC. Tumor mutation burden (TMB) refers to the total number of mutations in the coding region of the evaluated gene in the tumor cell (TC) genome, which is calculated by the total number of mutations per megabase in the genome (5)(6)(7). Previous reports suggested the close association of TMB with immune infiltration, while the molecular mechanism remains inconclusive (5)(6)(7).…”

Identification of the Real Hub Gene and Construction of a Novel Prognostic Signature for Pancreatic Adenocarcinoma Based on the Weighted Gene Co-expression Network Analysis and Least Absolute Shrinkage and Selection Operator Algorithms

“…We reason that the poorer prognosis of patients with PAAD in the high-risk subgroup could be attributed to the enhanced expression of immune checkpoints. It has been well established that higher expression of immune checkpoint molecules usually benefits more from immune checkpoint inhibitors (ICIs; Peng et al, 2021 ). Overall, these data indicate that patients with PAAD in the high-risk subgroup might have improved prognoses through the application of ICIs.…”

Biomarkers and Future Perspectives for Hepatocellular Carcinoma Immunotherapy

“…Recently, a five-gene immune-related signature ( LDHA , PPAT , BFSP1 , NR0B1 , and PFKFB4 ) was identified and used to establish a prognostic model for responses to HCC treatment that could stratify patients who were sensitive to immunotherapy ( 93 ). Other studies using different gene combination strategies have also reported their potential to predict ICI responses by reflecting the characteristics of the immune microenvironment ( 94 , 95 ). Nevertheless, these signatures need further testing for clinical application.…”