An Immune Signature Robustly Predicts Clinical Deterioration for Hepatitis C Virus-Related Early-Stage Cirrhosis Patients

Abstract

Hepatitis C virus (HCV)-related cirrhosis leads to a heavy global burden of disease. Clinical risk stratification in HCV-related compensated cirrhosis remains a major challenge. Here, we aim to develop a signature comprised of immune-related genes to identify patients at high risk of progression and systematically analyze immune infiltration in HCV-related early-stage cirrhosis patients. Bioinformatics analysis was applied to identify immune-related genes and construct a prognostic signature in microarray data set. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were conducted with the “clusterProfiler” R package. Besides, the single sample gene set enrichment analysis (ssGSEA) was used to quantify immune-related risk term abundance. The nomogram and calibrate were set up via the integration of the risk score and clinicopathological characteristics to assess the effectiveness of the prognostic signature. Finally, three genes were identified and were adopted to build an immune-related prognostic signature for HCV-related cirrhosis patients. The signature was proved to be an independent risk element for HCV-related cirrhosis patients. In addition, according to the time-dependent receiver operating characteristic (ROC) curves, nomogram, and calibration plot, the prognostic model could precisely forecast the survival rate at the first, fifth, and tenth year. Notably, functional enrichment analyses indicated that cytokine activity, chemokine activity, leukocyte migration and chemotaxis, chemokine signaling pathway and viral protein interaction with cytokine and cytokine receptor were involved in HCV-related cirrhosis progression. Moreover, ssGSEA analyses revealed fierce immune-inflammatory response mechanisms in HCV progress. Generally, our work developed a robust prognostic signature that can accurately predict the overall survival, Child-Pugh class progression, hepatic decompensation, and hepatocellular carcinoma (HCC) for HCV-related early-stage cirrhosis patients. Functional enrichment and further immune infiltration analyses systematically elucidated potential immune response mechanisms.

The Chemokine System in Oncogenic Pathways Driven by Viruses: Perspectives for Cancer Immunotherapy

“…While the role of chemokines in the clearance of acute HBV infection is less established [29], the timely mobilization of relevant immune cells and the increased expression of chemokines (e.g., primarily CXCR3 ligands) were also reported in HBV-positive hepatocytes and sera from infected patients [30]. On the other hand, the detrimental roles of chemokines and their receptors in the development and maintenance of chronic and uncontrolled inflammation that fosters fibrosis, cirrhosis, and HCC development are well known [31,32]. Several chemokines and receptors belong to the panel of genes whose expression levels in the liver of HCV-associated early-stage cirrhosis patients are significantly associated with the risk of progression [32].…”

“…On the other hand, the detrimental roles of chemokines and their receptors in the development and maintenance of chronic and uncontrolled inflammation that fosters fibrosis, cirrhosis, and HCC development are well known [31,32]. Several chemokines and receptors belong to the panel of genes whose expression levels in the liver of HCV-associated early-stage cirrhosis patients are significantly associated with the risk of progression [32]. As such, the upregulated expression of CXCL6, as a possible consequence of that of the bromodomain-containing protein 4, was proposed to participate in the development and progression of HBV-induced liver fibrosis [33].…”