ISG15 upregulation characterizes a PD-L1-associated immunosuppressive phenotype with CD8+ T-cell dysfunction in
Chao Lv1, Tao Liu2, Zhenhua Liu3
1Department of Hepatobiliary Surgery III, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China; Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing 400015, China.
Insights
Interferon-stimulated gene 15 (ISG15) is elevated in hepatocellular carcinoma (HCC), promoting immune evasion and poor prognosis. Targeting ISG15 may improve immunotherapy response in HCC patients.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune checkpoint inhibitors (ICIs) show potential for hepatocellular carcinoma (HCC) treatment, but immune evasion limits clinical efficacy.
- CD8+ T-cell dysfunction is a critical factor in HCC immune evasion.
- The role of Interferon-stimulated gene 15 (ISG15) in HCC immune suppression remains largely unknown.
Purpose of the Study:
- To investigate the role of ISG15 in HCC immune suppression.
- To evaluate ISG15 as a potential biomarker and therapeutic target in HCC immunotherapy.
Main Methods:
- Analysis of ISG15 expression in the TCGA-LIHC cohort, correlating it with prognosis and immune infiltration.
- Single-cell RNA sequencing to identify ISG15 expression in CD8+ T-cell subsets.
- In vitro studies using ISG15 overexpression and knockdown models to assess effects on CD8+ T-cell function and PD-L1 expression.
Main Results:
- ISG15 was found to be upregulated in HCC, correlating with poor prognosis and increased immune checkpoint gene expression.
- ISG15-enriched CD8+ T-cell subsets exhibited features of immune exhaustion.
- Tumor cell ISG15 overexpression impaired CD8+ T-cell viability, cytokine secretion, and cytotoxicity, partly via PD-L1 upregulation.
Conclusions:
- ISG15 is linked to an immunosuppressive tumor microenvironment in HCC.
- ISG15 may serve as a predictive biomarker for HCC immunotherapy.
- Targeting ISG15 presents a potential strategy to enhance HCC immunotherapy efficacy.
Background:
Immune checkpoint inhibitors (ICIs) show promise in hepatocellular carcinoma (HCC) treatment, but clinical responses remain limited due to immune evasion. CD8+ T-cell dysfunction is a key mechanism of immune evasion in HCC. Interferon-stimulated gene 15 (ISG15), a ubiquitin-like modifier, is implicated in tumor progression, but its role in immune suppression in HCC is unclear.
Methods:
ISG15 expression was analyzed in the TCGA-LIHC cohort, and its correlation with prognosis, immune infiltration, and checkpoint-related gene expression was evaluated. Single-cell RNA sequencing identified ISG15 expression in CD8+ T-cell subsets. Immunohistochemistry and multiplex immunofluorescence were performed on clinical HCC samples, focusing on tumor recurrence. In vitro, ISG15 overexpression and knockdown models in HepG2 and MHCC97L cells assessed effects on CD8+ T-cell viability, cytokine production, and cytotoxic activity. PD-L1 blockade assays were performed in the ISG15-overexpression group to assess the functional involvement of PD-L1.
Results:
ISG15 was upregulated in HCC and was associated with poor prognosis, higher TIDE scores, and increased immune checkpoint gene expression. Single-cell analysis identified ISG15-enriched CD8+ T-cell subsets with IFN/ISG-related and exhaustion-associated features. In co-culture assays, tumor-cell ISG15 overexpression was associated with reduced CD8+ T-cell viability, cytokine secretion, and cytotoxicity, together with increased PD-L1 expression and anti-apoptotic proteins. PD-L1 blockade partially restored CD8+ T-cell effector function.
Conclusions:
ISG15 is associated with an immunosuppressive phenotype in HCC and may represent a candidate biomarker and potential target for further investigation in HCC immunotherapy.
