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

Flint, E. E.; Ercan, C.; Mitchell, E.; Pop, O. T.; Geng, A.; Jorzik, P.; Possamai, L. A.; Brenig, R. G.; Morel, S.; Sieber, P.; Singanayagam, A.; Matter, M. S.; Semela, D.; Heim, M. H. E.; Demougin, P.; Roux, J.; Terracciano, L. M.; Triantafyllou, E.; Bernsmeier, C.

doi:10.1101/2024.03.29.587228

bioRxiv · 10.1101/2024.03.29.587228

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

Flint, E. E.·Ercan, C.·Mitchell, E.·Pop, O. T.·Geng, A.·Jorzik, P.·Possamai, L. A.·Brenig, R. G.·Morel, S.·Sieber, P.·Singanayagam, A.·Matter, M. S.·Semela, D.·Heim, M. H. E.·Demougin, P.·Roux, J.·Terracciano, L. M.·Triantafyllou, E.·Bernsmeier, C.

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Abstract

Background 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 by ex vivo polyinosinic: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 assessed ex 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-MDSC ex vivo. Circulating and hepatic MDSC expanded in our murine models of liver fibrosis and suppressed T-cell proliferation. Lipopolysaccharide and E.coli challenge exacerbated hepatic MDSC and fibrosis compared to CCl4 controls. 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-MDSC ex 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.

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Flint, E. E., Ercan, C., Mitchell, E., Pop, O. T., Geng, A., Jorzik, P., Possamai, L. A., Brenig, R. G., Morel, S., Sieber, P., Singanayagam, A., Matter, M. S., Semela, D., Heim, M. H. E., Demougin, P., Roux, J., Terracciano, L. M., Triantafyllou, E., Bernsmeier, C.. 2024-04-01. Targeting the expansion of myeloid-derived suppressor cells in liver cirrhosis. https://doi.org/10.1101/2024.03.29.587228

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