Hepatic regulatory T-cells promote colorectal liver metastasis in NASH

Abstract

Abstract Background: Non-alcoholic steatohepatitis (NASH), a progressive inflammatory form of NAFLD, underlies an extremely versatile and dynamic inflammatory microenvironment along with aberrant metabolism and ongoing liver regeneration. Regulatory T cells (Tregs), as essential immune regulatory cells, are critical for the inhibition of tumor-promoting inflammation and cancer cell escape. Our recent study found that Tregs were selectively increased in both mouse models and patients with NAFLD, which promotes us to study the role of Tregs in NASH-HCC. However, the role of Tregs in the development of hepatic metastasis in NASH liver remains unknown. Methods: A Western diet mouse model and the STAM mouse model were utilized for NASH development. MC38 murine colorectal tumor cells were injected via portal vein at 12 weeks of feeding or orthotopically injected into cecum subserosa. Tumor development will be determined 3 or 4 weeks after injection. Depletion of Tregs by FoxP3-DTR mice or CD25 antibody treatment. Transcriptomic profiling of leucocytes in hepatic immune microenvironment was determined by scRNA-seq. Results: There is a positive correlation between increased Tregs and hepatic tumor growth in NASH liver. Depleting Tregs inhibits the development of hepatic metastasis in NASH liver compared with control liver. NASH development led to a significant transcriptomic shift in hepatic immune cells, such as Kupffer cells, Tregs and MDSCs. Blocking the interaction of Tregs and PMN-MDSCs in the TME prevents tumor growth in the NASH liver. Conclusions: Tregs can suppress immunosurveillance in the premalignant stages of NASH. Therapies targeting Tregs could offer a potential strategy for preventing hepatic metastasis in patients with NASH. RO1GM137203