A Unique Immune-Related Gene Signature Represents Advanced Liver Fibrosis and Reveals Potential Therapeutic Targets

Abstract

Innate and adaptive immune responses are critically associated with the progression of fibrosis in chronic liver diseases. In this study, we aim to identify a unique immune-related gene signature representing advanced liver fibrosis and to reveal potential therapeutic targets. Seventy-seven snap-frozen liver tissues with various chronic liver diseases at different fibrosis stages (1: n = 12, 2: n = 12, 3: n = 25, 4: n = 28) were subjected to expression analyses. Gene expression analysis was performed using the nCounter PanCancer Immune Profiling Panel (NanoString Technologies, Seattle, WA, USA). Biological meta-analysis was performed using the CBS Probe PINGSTM (CbsBioscience, Daejeon, Korea). Using non-tumor tissues from surgically resected specimens, we identified the immune-related, five-gene signature (CHIT1_FCER1G_OSM_VEGFA_ZAP70) that reliably differentiated patients with low- (F1 and F2) and high-grade fibrosis (F3 and F4; accuracy = 94.8%, specificity = 91.7%, sensitivity = 96.23%). The signature was independent of all pathological and clinical features and was independently associated with high-grade fibrosis using multivariate analysis. Among these genes, the expression of inflammation-associated FCER1G, OSM, VEGFA, and ZAP70 was lower in high-grade fibrosis than in low-grade fibrosis, whereas CHIT1 expression, which is associated with fibrogenic activity of macrophages, was higher in high-grade fibrosis. Meta-analysis revealed that STAT3, a potential druggable target, highly interacts with the five-gene signature. Overall, we identified an immune gene signature that reliably predicts advanced fibrosis in chronic liver disease. This signature revealed potential immune therapeutic targets to ameliorate liver fibrosis.

Pien-Tze-Huang alleviates CCl4-induced liver fibrosis through the inhibition of HSC autophagy and the TGF-β1/Smad2 pathway

“…Liver fibrosis is a sophisticated lesion implicated in multiple cells, pathways, and molecules (Sung et al, 2022).…”

Multiplexed Digital Spatial Protein Profiling Reveals a Unique Protein Signature for Advanced Liver Fibrosis

“…It also found that CD68 + macrophages were predominantly concentrated in scars during advanced brosis, suggesting its probrogenic role in the process of liver brosis. [4,24] HLA-DR is routinely used to identify macrophage lineages such as Kupffer cells and circulating macrophages. [25] HLA-DR is also a typical marker for macrophages and is widely present in antigen-presenting cells.…”

“…The nCounter PanCancer Immune Pro ling Panel (NanoString Technologies) was used for gene set pro ling as previously described. [4] Tissue microarray (TMA) construction TMAs were constructed using 2-mm diameter cores punched from formalin-xed, para n-embedded (FFPE) blocks. The TMA blocks were sectioned 5-mmthick.…”

“…[3] A very recent study from our group also recently presented a promising immune-related gene signature for predicting advanced brosis. [4] Although several approaches to reduce brosis are still under investigation, no drug has yet been demonstrated to be effective in reversing brosis.…”

Blood-based biomarkers for immune-based therapy in advanced HCC: Promising but a long way to go

“…Regardless of the underlying causes associated with HCC, inflammation remains a major factor, especially because the evolution of hepatic fibrosis to neoplasia may rely on several intra-hepatic proinflammatory cascades ( 14 , 66 ). In general, adverse survival statistics and the cancer progression is frequently associated with systemic inflammation ( 67 ).…”