CD8 T Cell Hyperfunction and Reduced Tumour Control in Murine Models of Advanced Liver Disease

TL;DR

Mice with advanced liver disease show overactive CD8 T cells that fail to respond well to tumors and immunotherapy.

Contribution

This study identifies prolonged CD8 T cell dysfunction in murine models of advanced liver disease, linking it to impaired antitumor immunity.

Findings

CD8 T cells in mice with advanced fibrosis show IFN-γ and granzyme B hyperfunction.

These mice have impaired responses to tumor challenges and immunotherapy.

Hyperfunction persists even after liver damage stops.

Abstract

Immune dysfunction in liver disease contributes to significant morbidities, depending on liver damage severity and aetiology. We previously reported long‐lasting generalized CD8 T cell hyperfunction in chronic HCV infection with advanced fibrosis, yet its separation from viral and fibrosis‐driven effects, as well as clinical outcomes of advanced fibrosis, remains unclear. In a murine model of carbon tetrachloride‐induced progressive liver fibrosis, advanced fibrosis was observed by 12 weeks, with pathologies similar to those of human chronic HCV infection. Blood‐circulating CD8 T cells showed IFN‐γ and granzyme B (GrB) hyperfunction in response to anti‐CD3/28 stimulation, as well as impaired responses to ectopic tumour challenge and anti‐PD‐1/CTLA‐4 immunotherapy. Hyperfunction and impaired tumour responses were retained despite liver insult cessation. In a 45% HFD model, which induced steatosis and minimal fibrosis, IFN‐γ and GrB hyperfunction was also observed in blood‐circulating CD8 T cells. This study highlights a prolonged systemic CD8 T cell dysfunction acquired during progressive liver disease, associated with impaired antitumour and immunotherapy responses. These mirror the bulk CD8 T cell dysfunction observed in advanced liver diseases in humans, suggesting that these models could be valuable for future mechanistic studies aimed at identifying targets to help improve clinical outcomes in chronic liver disease.

Blood CD8 T cells in mice with advanced liver fibrosis exhibit IFN‐γ and granzyme B hyperfunction, and animal responses to ectopic tumour challenge and immunotherapy are impaired.

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