Abstract
The liver hosts a unique immune landscape, enriched in natural killer (NK) cells that are critical for antiviral defense. In chronic hepatitis B virus (HBV) infection, their role within the intrahepatic compartment remains incompletely understood. In this thesis, we investigated how HBV shapes liver immunity, with a particular focus on NK cell function, and explored immune-based biomarkers for the early detection of hepatocellular carcinoma (HCC).
In the first part, we applied fine-needle aspiration (FNA) sampling and advanced multiplex immunofluorescence to profile intrahepatic immunity in chronic HBV. We identified liver-resident CXCR6⁺ NK cells as the dominant in situ producers of interferon-γ (IFN-γ) in healthy liver. In NUC-treated HBV, these cells were numerically reduced and showed markedly diminished IFN-γ production despite preserved cytotoxicity. This defect was not observed in circulating NK cells and was accompanied by reduced dendritic cell–recruiting chemokines, highlighting a liver-specific bottleneck in antiviral immunity. We also observed an association between hepatitis B surface antigen (HBsAg) levels and CXCR6⁺ NK cell frequency; however, the apparent impact of this viral antigen was unexpectedly limited.
The second part focused on the early detection of HCC, a major complication of chronic HBV and other liver diseases. We developed and validated the ASAP model, a simple and low-cost blood-based biomarker panel that outperformed existing methods in European and South American cohorts. In addition, we evaluated virological (e.g., HBcrAg) and immunological (e.g., cytokines) markers, demonstrating that persistent low-grade inflammation can predict HCC risk even in the absence of cirrhosis.
Together, these studies demonstrate that immune alterations in HBV and early HCC are localized to the liver and often remain undetectable in peripheral blood. Targeting intrahepatic immune restoration, particularly of NK cells, alongside implementing accessible early detection strategies, could improve both disease control and cancer prevention.
In the first part, we applied fine-needle aspiration (FNA) sampling and advanced multiplex immunofluorescence to profile intrahepatic immunity in chronic HBV. We identified liver-resident CXCR6⁺ NK cells as the dominant in situ producers of interferon-γ (IFN-γ) in healthy liver. In NUC-treated HBV, these cells were numerically reduced and showed markedly diminished IFN-γ production despite preserved cytotoxicity. This defect was not observed in circulating NK cells and was accompanied by reduced dendritic cell–recruiting chemokines, highlighting a liver-specific bottleneck in antiviral immunity. We also observed an association between hepatitis B surface antigen (HBsAg) levels and CXCR6⁺ NK cell frequency; however, the apparent impact of this viral antigen was unexpectedly limited.
The second part focused on the early detection of HCC, a major complication of chronic HBV and other liver diseases. We developed and validated the ASAP model, a simple and low-cost blood-based biomarker panel that outperformed existing methods in European and South American cohorts. In addition, we evaluated virological (e.g., HBcrAg) and immunological (e.g., cytokines) markers, demonstrating that persistent low-grade inflammation can predict HCC risk even in the absence of cirrhosis.
Together, these studies demonstrate that immune alterations in HBV and early HCC are localized to the liver and often remain undetectable in peripheral blood. Targeting intrahepatic immune restoration, particularly of NK cells, alongside implementing accessible early detection strategies, could improve both disease control and cancer prevention.
| Original language | English |
|---|---|
| Awarding Institution |
|
| Supervisors/Advisors |
|
| Award date | 3 Sept 2025 |
| Place of Publication | Rotterdam |
| Print ISBNs | 978-94-6510-836-0 |
| Publication status | Published - 3 Sept 2025 |
