The role of Th2 in immune surveillance of NAFLD-associated liver metastasis

Abstract

Abstract Non-alcoholic fatty liver disease (NAFLD) is an increasing global epidemic associated with chronic inflammation, metabolic disorders, immunosuppression and importantly, increased incidence of primary and metastatic liver cancers. We have recently demonstrated that the immunosuppressive nature of NAFLD livers represented by increased myeloid-derived suppressor cells and dysregulated natural-killer T cells, resulted in aggressive tumorigenesis and immunotherapy resistance of primary liver cancer. Given the importance of metabolic and immune imbalance in the formation of metastatic-prone liver microenvironment, we continued to dissect the cellular complexity of NAFLD livers in metastatic liver cancers. Through bulk and single-cell RNA-sequencing (scRNA-seq) dataset analysis from mice and patients with NAFLD or liver metastasis (LM), we found that the CD4 +T helper-2 (Th2) population and the regulon activity of its master transcription factor GATA3were also remarkably reduced in NAFLD or LM compared to healthy controls. Interestingly, increased hepatic metastasis was observed in mice with NAFLD induced by high-fed-high-carbohydrate-diet compared to controlled mice by orthotopic LM mouse models, accompanied with reduced hepatic Th2 cells which negatively correlated with increased triglyceride and cholesterol levels. Taken together, our preliminary findings suggested a potential immunosurveillance role of hepatic Th2 cells that may be dysregulated by lipid metabolic alterations in NAFLD. Therapeutic approaches to restore hepatic Th2 cells may therefore provide new perspective and therapeutic approaches to reduce liver metastasis in the era of NAFLD epidemic. The project is supported by RGC/GRF14104820. The project is supported by RGC/GRF14104820.