Lymphocytes play a role in chronic liver injury and tumorigenesis, yet decrease overall mortality.
Major finding: Lymphocytes play a role in chronic liver injury and tumorigenesis, yet decrease overall mortality.
Mechanism: CD8+ T cells and LTβ receptor signaling induce HCC in response to chronic liver damage.
Impact: Tight regulation of the immune system is required to balance immune surveillance with cancer risk.
Hepatocellular carcinoma (HCC) is linked to inflammation, and sustained inflammation can promote liver fibrosis and cirrhosis as well as malignant transformation. However, the liver contains numerous immune cells that can suppress tumorigenesis. Endig, Buitrago-Molina, Marhenke, and colleagues used the Fah−/− mouse, which models the inflammatory environment of chronic liver disease, to elucidate the role of immune cells in chronic liver injury and carcinogenesis. Liver injury resulted in activation of immune cells, including increased CD4+ and CD8+ T cells. In response to repeated liver damage, approximately 70% of Fah−/−;Rag2−/−;Il2rγ−/− (FCR) mice, which lack all lymphoid cells, died in the first 2 months, whereas the majority of Fah−/− mice survived repeated liver damage over 121 days, indicating that the adaptive immune system is important for survival during chronic liver injury. Surviving Fah−/− mice exhibited more severe liver injury and fibrosis than surviving FCR mice, suggesting that the adaptive immune system promotes fibrosis in addition to promoting survival in response to liver damage. After several cycles of induced liver damage Fah−/− mice all developed HCC, whereas only 12% of FCR mice developed tumors, demonstrating that the adaptive immune cells promote hepatocarcinogenesis. CD8+ T cells were responsible for the effects, as adoptive transfer of CD8+ T cells in FCR mice was sufficient to protect against acute liver failure, and CD8+ T cells were also required for the development of HCC. Treatment of Fah−/− mice with cyclosporine A, an immunosuppressive drug that blocks T-cell activation and expansion, resulted in reduced tumor burden. Fah−/− mice exhibited increased expression of lymphotoxin-β (LT β) compared with FCR mice, and blocking LTβ receptor signaling suppressed tumor formation. Altogether, these findings reveal a context-dependent dual role for the adaptive immune system in promoting and suppressing HCC, as well as in promoting fibrosis and protecting against liver failure.