Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion

The tumor microenvironment, which consists of fibroblasts, smooth muscle cells, endothelial cells, immune cells, epithelial cells, and extracellular matrices, plays a crucial role in tumor progression. Hepatic stellate cells (HSCs), a class of unique liver stromal cells, participate in immunomodulatory activities by inducing the apoptosis of effector T-cells, generation of regulatory T-cells, and development of myeloid-derived suppressor cells (MDSCs) to achieve long-term survival of islet allografts. This study provides in vitro and in vivo evidences that HSCs induce the generation of MDSCs to promote hepatocellular carcinoma (HCC) progression through interleukin (IL)-6 secretion. HSC-induced MDSCs highly expressed inducible nitric oxide synthase (iNOS) and arginase 1 mRNA and presented potent inhibitory T-cell immune responses in the tumor environment. Wild-type HSC-induced MDSCs expressed lower levels of CD40, CD86, and MHC II, and a higher level of B7-H1 surface molecules, as well as increased the production of iNOS and arginase I compared with MDSCs induced by IL-6-deficient HSCs in vitro. A murine-transplanted model of the liver tumor showed that HCCs cotransplanted with HSCs could significantly enhance the tumor area and detect more MDSCs compared with HCCs alone or HCCs cotransplanted with HSCs lacking IL-6. In conclusion, the results indicated that MDSCs are induced mainly by HSCs through IL-6 signaling and produce inhibitory enzymes to reduce T-cell immunity and then promote HCC progression within the tumor microenvironment. Therapies targeting the pathway involved in MDSC production or its immune-modulating pathways can serve as an alternative immunotherapy for HCC.

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P135 DEPLETION OF H2O2 BY CATALASE INDUCES MYELOID-DERIVED SUPPRESSOR CELLS – A NOVEL MECHANISM OF IMMUNE-REGULATION BY HEPATIC STELLATE CELLS

Journal of Hepatology ◽

10.1016/s0168-8278(14)60297-x ◽

2014 ◽

Vol 60 (1) ◽

pp. S110-S111

Author(s):

Y.J. Resheq ◽

K.-K. Li ◽

S. Wards ◽

A. Wilhelm ◽

A. Garg ◽

...

Keyword(s):

Immune Regulation ◽

Hepatic Stellate Cells ◽

Suppressor Cells ◽

Stellate Cells ◽

Myeloid Derived Suppressor Cells

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Hepatic stellate cells induce myeloid derived suppressor cells

Zeitschrift für Gastroenterologie ◽

10.1055/s-0032-1332113 ◽

2013 ◽

Vol 51 (01) ◽

Author(s):

B Höchst ◽

FA Schildberg ◽

P Sauerborn ◽

LC Heukamp ◽

M Ballmeier ◽

...

Keyword(s):

Hepatic Stellate Cells ◽

Suppressor Cells ◽

Stellate Cells ◽

Myeloid Derived Suppressor Cells

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Generation of Immunosuppressive Antigen Presenting Cells with the Phenotype and Function of Myeloid Derived Suppressor Cells

Blood ◽

10.1182/blood.v120.21.1032.1032 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1032-1032

Author(s):

Stefanie AE Held ◽

Annkristin Heine ◽

Julia Wolf ◽

Solveig Daecke ◽

Anita Bringmann ◽

...

Keyword(s):

Peripheral Blood ◽

Suppressor Cells ◽

Blood Monocytes ◽

Inhibitory Effects ◽

Peripheral Blood Monocytes ◽

Gm Csf ◽

Hla Dr ◽

Stimulatory Capacity ◽

And Function ◽

Antigen Presenting

Abstract Abstract 1032 Myeloid derived suppressor cells (MDSC) play an important role in the regulation of immune responses by suppressing the function of antigen presenting cells and T cells. In humans several populations of MDSC with different phenotypes were characterized due to their distinct immunosuppressive function. However, the origin and development of these cells is not well understood. We observed that incubation of peripheral blood monocytes with IL-10 during their differentiation to dendritic cells (DC) in the presence of GM-CSF and IL-4 results in the generation of an APC population with dramatically reduced stimulatory capacity and a CD14+ and HLA-DR low phenotype (IL-10-APC) similar to the recently described human MDSC subpopulation. In coincubation experiments we found that the addition of these cells to immature or LPS activated DC generated from peripheral blood monocytes resulted in a cell number dependent inhibition of their stimulatory capacity in the mixed lymphocyte reaction assay. Furthermore, these IL-10-APCs reduced the expression of CD1a and costimulatory molecules on DC as well as their activation by LPS characterized by diminished expression of maturation markers including CD83, CD80, CD86 or CD40. IL-10-APC almost completely abolished the secretion of cytokines and chemokines by mature and immature DC involved in T cell stimulation and migration such as TNF-a, IL-6, MIP-1a or Rantes. These effects were not due to induction of IL-10 production and were not observed when purified CD14+ monocytes were used as a control in the experiments. In order to analyze the possible mechanisms and molecules involved in these inhibitory effects we found that IL-10-APC expressed higher levels of PD-1, GITR, GITRL and osteoactivin, an immunosuppressive molecule that was shown to inhibit the function of T cells. The effects mediated by these molecules were further confirmed by utilizing blocking antibodies. Interestingly, addition of IL-10-APC to mature or immature DC induced an increased expression of osteoactivin and its corresponding receptor syndecan 4 on DC thus demonstrating that osteoactivin mediates its effects by upregulating its own receptor. In the next set of experiments we isolated the CD14+ HLA-DR low cell population from buffy coats of healthy donors. We found, that these cells similar to the IL-10-APCs express high levels of osteoactivin and syndecan-4 that can be further upregulated by the addition of IL-10. Our results demonstrate that osteoactivin mediates its inhibitory effects by induction of its cognate receptor syndecan 4. In addition, cells with the phenotype and function of MDSC can differentiate from human peripheral blood monocytes in the presence of GM-CSF, IL-4 and IL-10. This immunosuppressive cell population can easily be generated in vitro and might be applied for the treatment of patients with GVHD or autoimmune disorders. Disclosures: No relevant conflicts of interest to declare.

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Characterization of Monocyte-Associated Factor V

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649565 ◽

1993 ◽

Vol 70 (02) ◽

pp. 273-280 ◽

Cited By ~ 5

Author(s):

Janos Kappelmayer ◽

Satya P Kunapuli ◽

Edward G Wyshock ◽

Robert W Colman

Keyword(s):

Monoclonal Antibody ◽

Light Chain ◽

Peripheral Blood ◽

De Novo ◽

Factor V ◽

Blood Monocytes ◽

De Novo Synthesis ◽

Hep G2 ◽

Hep G2 Cells ◽

Peripheral Blood Monocytes

SummaryWe demonstrate that in addition to possessing binding sites for intact factor V (FV), unstimulated peripheral blood monocytes also express activated factor V (FVa) on their surfaces. FVa was identified on the monocyte surface by monoclonal antibody B38 recognizing FVa light chain and by human oligoclonal antibodies H1 (to FVa light chain) and H2 (to FVa heavy chain) using immunofluorescence microscopy and flow cytometry. On Western blots, partially cleaved FV could be identified as a 220 kDa band in lysates of monocytes. In addition to surface expression of FVa, monocytes also contain intracellular FV as detected only after permeabilization by Triton X-100 by monoclonal antibody B10 directed specifically to the Cl domain not present in FVa. We sought to determine whether the presence of FV in peripheral blood monocytes is a result of de novo synthesis.Using in situ hybridization, no FV mRNA could be detected in monocytes, while in parallel control studies, factor V mRNA was detectable in Hep G2 cells and CD18 mRNA in monocytes. In addition, using reverse transcriptase and the polymerase chain reaction, no FV mRNA was detected in mononuclear cells or in U937 cells, but mRNA for factor V was present in Hep G2 cells using the same techniques. These data suggest that FV is present in human monocytes, presumably acquired by binding of plasma FV, and that the presence of this critical coagulation factor is not due to de novo synthesis.

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