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NAFLD indirectly impairs antigen-specific CD8+ T cell immunity against liver cancer in mice
John C McVey1,2, Benjamin L Green1,3, Benjamin Ruf1
1Gastrointestinal and Thoracic Malignancy Section, National Cancer Institute, National Institutes of Health, TGMB NIH/NCI/CCR Building 10 Rm 3B44 9000 Rockville Pike, Bethesda, MD, USA.
Abstract:
Non-alcoholic fatty liver disease (NAFLD) has become an important etiology leading to liver cancer. NAFLD alters adaptive T cell immunity and has a profound influence on liver cancer development. However, it is unclear how NAFLD affects tumor antigen-specific T cell response. In this study, we generated a doxycycline-inducible MHC-I and -II antigen-expressing HCC cell line which allowed us to investigate tumor antigen-specific T cell response in two NAFLD mouse models. The system proved to be an effective and efficient way to study tumor antigen-specific T cells. Using this model, it was found that NAFLD impairs antigen-specific CD8+ T cell immunity against HCC. The effect was not due to reduced generation or intrinsic functional changes of tumor antigen-specific CD8+ T cells but caused by accumulated macrophages in the liver environment. The findings suggest that targeting macrophages in NAFLD-driven HCC may improve therapeutic outcomes.
Insights
Non-alcoholic fatty liver disease (NAFLD) impairs the immune system's ability to fight liver cancer. Accumulated macrophages in the liver, not T-cells, hinder this anti-cancer response in NAFLD.
Area of Science:
- Hepatology
- Immunology
- Oncology
Background:
- Non-alcoholic fatty liver disease (NAFLD) is a growing cause of liver cancer.
- NAFLD impacts adaptive T cell immunity, influencing liver cancer progression.
- The specific effects of NAFLD on tumor antigen-specific T cell responses remain unclear.
Purpose of the Study:
- To investigate how NAFLD affects tumor antigen-specific T cell responses in hepatocellular carcinoma (HCC).
- To develop and utilize a novel system for studying T cell immunity in NAFLD-associated HCC models.
Main Methods:
- Generation of a doxycycline-inducible MHC-I and -II antigen-expressing HCC cell line.
- Utilized two NAFLD mouse models to study tumor antigen-specific T cell responses.
- Assessed CD8+ T cell immunity and the role of liver macrophages in NAFLD-driven HCC.
Main Results:
- NAFLD was found to impair antigen-specific CD8+ T cell immunity against HCC.
- This impairment was not due to issues with T cell generation or intrinsic function.
- Accumulated macrophages within the liver microenvironment were identified as the cause of impaired T cell immunity.
Conclusions:
- NAFLD negatively impacts anti-tumor CD8+ T cell immunity in HCC.
- Liver macrophages play a critical role in mediating this immune suppression.
- Targeting macrophages presents a potential therapeutic strategy for NAFLD-driven HCC.
