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CD8 T Cell Hyperfunction and Reduced Tumour Control in Murine Models of Advanced Liver Disease
Jood Madani1,2,3, Jiafeng Li1,2,3, Ma Enrica Angela Ching4
1Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.
European Journal of Immunology
|August 5, 2025
Summary
Progressive liver disease causes long-lasting CD8 T cell dysfunction, impairing anti-tumor responses and immunotherapy effectiveness. This immune dysfunction persists even after the liver insult stops, impacting chronic liver disease outcomes.
Area of Science:
- Immunology
- Hepatology
- Oncology
Background:
- Liver disease causes immune dysfunction, impacting morbidity.
- Chronic Hepatitis C (HCV) infection with advanced fibrosis shows long-lasting CD8 T cell hyperfunction.
- The precise role of viral and fibrosis-driven effects on CD8 T cell dysfunction and clinical outcomes in advanced fibrosis is unclear.
Purpose of the Study:
- To investigate systemic CD8 T cell dysfunction in murine models of progressive liver disease.
- To determine if CD8 T cell hyperfunction and impaired anti-tumor responses persist after liver insult cessation.
- To assess CD8 T cell responses in a non-alcoholic fatty liver disease model.
Main Methods:
- Carbon tetrachloride-induced progressive liver fibrosis model in mice.
- High-fat diet (HFD) model inducing steatosis and minimal fibrosis.
- Assessment of CD8 T cell function (IFN-γ, Granzyme B) via stimulation and response to tumor challenge and immunotherapy (anti-PD-1/CTLA-4).
Main Results:
- Advanced fibrosis induced CD8 T cell hyperfunction (IFN-γ, GrB) and impaired anti-tumor/immunotherapy responses.
- These CD8 T cell dysfunctions persisted after cessation of liver insult.
- Steatosis and minimal fibrosis also induced CD8 T cell hyperfunction.
Conclusions:
- Progressive liver disease leads to prolonged systemic CD8 T cell dysfunction.
- This dysfunction is associated with impaired anti-tumor immunity and immunotherapy efficacy.
- Murine models of liver disease are valuable for studying CD8 T cell dysfunction in chronic liver disease.
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