CD8 T cell hyperfunction and reduced tumour control in models of advanced liver fibrosis

Abstract

Immune dysfunction, both depression and hyperactivation, in liver disease contributes to significant morbidities and mortalities, depending on liver damage severity and etiology. The underlying causes of immune dysfunction in advanced liver disease, whether pathogen or host-mediated, remain unclear. We reported lasting generalized CD8 T cell hyperfunction in individuals with advanced liver fibrosis in chronic HCV infection. The separation of viral and fibrosis-driven effects or the association of this phenomenon with clinical outcomes of advanced liver fibrosis remains to be determined. Here, a hepatotoxic murine model of liver fibrosis was used to decouple liver fibrosis from viral infection. Carbon tetrachloride (CCl4)-treated mice presented progressive liver fibrosis within ≈12 weeks, resulting in severe diffuse fibrosis, focal necrosis and surrounding mixed inflammation; pathology similar to that of chronic HCV infection. Taking advantage of this model, we investigated if liver fibrosis caused systemic CD8 T cell hyperfunction and evaluated its impact on host immune response. At peak liver fibrosis, circulating CD8+ T cells presented increased expression of IFN-γ and granzyme B (GrB) in comparison to control animals. CD8 T cell hyperfunction arose by 8 weeks of CCl4treatment and was sustained with continued liver insult. As a result, fibrotic mice were unable to resist an ectopic tumour challenge and were less responsive to immunotherapy. Furthermore, CD8 T cell dysfunction was observed in other contexts of chronic liver insult such as high fat diet-induced liver steatosis, even in the absence of significant fibrosis. Collectively, this study shows the impact of chronic liver insult on systemic CD8 T cell function and its association with impaired immune response, such as tumour surveillance.