Targeting the expansion of myeloid-derived suppressor cells in liver cirrhosis

Abstract

AbstractBackground and aimsPreviously, we identified immune-suppressive circulating monocytic myeloid-derived suppressor cells (M-MDSC) in patients with cirrhosis and liver failure, which increased with disease severity and were associated with infections and mortality. Impaired immune responses and M-MDSC expansion were reversed byex vivopolyinosinic:polycytidylic acid (poly(I:C)) treatment. Here, we aimed to investigate hepatic MDSC subsets in liver biopsies of cirrhotic patients and identify MDSC subsets in murine models to assess the safety and efficacy of poly(I:C)in vivo.Methods22 cirrhotic patients and 4 controls were clinically characterised. MDSC were identified in liver biopsies (immunofluorescence) and in the circulation (flow cytometry). M- MDSC phenotype and function following poly(I:C) stimulation were assessedex vivo. Carbon tetrachloride-based murine models of liver fibrosis were used. Poly(I:C) was administered therapeutically. MDSC biology was investigated with flow cytometry, immunofluorescence and T-cell proliferation assay. Hepatic histopathology, transcriptomics (BulkRNAseq) and serum markers were assessed.ResultsBesides circulating M-MDSC, hepatic CD14+CD84+M-MDSC and CD15+CD84+polymorphonuclear-MDSC expanded in cirrhotic patients and indicated disease severity, infections and poor survival. Poly(I:C) treatment reversed phenotype and function of circulating M-MDSCex vivo. Circulating and hepatic MDSC expanded in our murine models of liver fibrosis and suppressed T-cell proliferation. Lipopolysaccharide andE.colichallenge exacerbated hepatic MDSC and fibrosis compared to CCl4controls. Poly(I:C) therapy reduced MDSC expansion in fibrotic mice with bacterial infection and CCl4-induced fibrosis.ConclusionHepatic MDSC expanded in cirrhotic patients and were linked with disease severity and poor prognosis. Poly(I:C) reversed frequency and function of M-MDSCex vivo. Poly(I:C) therapy reversed MDSC expansion and fibrosis in a murine model of liver fibrosis with infection. Thus, we highlighted poly(I:C) as a potential immunotherapy for the treatment of immuneparesis in cirrhosis.