Hepatic stellate cells induce myeloid derived suppressor cells

Both inflammation and immune suppression are implicated to play a role in tumorigenesis and progression. Myeloid derived suppressor cells (MDSCs) are associated with both inflammation and suppression of immunity. However, little is known about how or where MDSCs are induced and from which cells they originate. The liver is known for its unique immune regulatory function. Here, we investigated the relevance of the interaction of human hepatic stellate cells (HSCs) with peripheral blood monocytes for development of MDSCs. Culturing freshly isolated human monocytes on primary HSCs we were able to characterized the phenotype and function of resulting CD14+HLA-DR-/low monocytes by flow cytometry, quantitative PCR and functional assays. We analyzed the molecular mechanisms underlying the induction and function of the CD14+HLA-DR-/low cells by using blocking antibodies, inhibitors or knock down technology. Mature peripheral blood monocytes co-cultured with HSCs down-regulated HLA-DR and developed a phenotypic and functional profile similar to MDSCs. Such CD14+HLA-DR-/low monocyte/MDSCs suppressed T cell proliferation in an arginase-dependent fashion. HSC-induced development of CD14+HLA-DR-/low monocytes/MDSCs was not mediated by soluble factors but required physical interaction. Our study shows that human HSCs convert mature peripheral monocytes into MDSCs. HSC-induced CD14+HLA-DR-/low monocytes were functionally and phenotypically similar to MDSCs isolated from liver cancer patients. Thus, our data suggest that local generation of MDSCs by liver-resident HSCs contribute to immune suppression in the liver.