Generation and functional characterization of MDSC-like cells. (3rd April 2017)

• Record Type: Journal Article
• Authors: Heine, Annkristin; Held, Stefanie Andrea Erika; Schulte-Schrepping, Jonas; Wolff, Julia Friederike Andrea; Klee, Kathrin; Ulas, Thomas; Schmacke, Niklas Arndt; Daecke, Solveig Nora; Riethausen, Kati; Schultze, Joachim L.; Brossart, Peter
• Is Part Of: Oncoimmunology. Volume 6:Number 4(2017)
• Publication Date: 2017-04-03
• Subjects: APC -- GITR -- IL-10 -- immunosuppression -- MDSC -- osteoactivin -- PD-1 -- PD-L1 -- syndecan-4; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2017.1295203
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: Myeloid-derived suppressor cells (MDSC) are critical in regulating immune responses by suppressing antigen presenting cells (APC) and T cells. We previously observed that incubation of peripheral blood monocytes with interleukin (IL)-10 during their differentiation to monocyte-derived dendritic cells (moDCs) results in the generation of an APC population with a CD14 + HLA-DR low phenotype (IL-10-APC) with reduced stimulatory capacity similar to human MDSC. Co-incubation experiments now revealed that the addition of IL-10-APC to moDC caused a reduction of DC-induced T-cell proliferation, of the expression of maturation markers, and of secreted cytokines and chemokines such as TNF-α, IL-6, MIP-1α and Rantes. Addition of IL-10-APC increased the immunosuppressive molecule osteoactivin and its corresponding receptor syndecan-4 on moDC. Moreover, CD14 + HLA-DR low MDSC isolated from healthy donors expressed high levels of osteoactivin, which was even further upregulated by the auxiliary addition of IL-10. Using transcriptome analysis, we identified a set of molecules and pathways mediating these effects. In addition, we found that IL-10-APC as well as human isolated MDSC expressed higher levels of programmed death (PD)-1, PD-ligand-1 (PD-L1), glucocorticoid-induced-tumor-necrosis-factor-receptor-related-protein (GITR) and GITR-ligand. Inhibition of osteoactivin, syndecan-4, PD-1 or PD-L1 on MDSC by using blocking antibodies restored the stimulatory capacity of DC in co-incubation experiments. Activation of MDSC with Dectin-1 ligand curdlan reduced the expression of osteoactivin and PD-L1. Our results demonstrate that osteoactivin/syndecan-4 and PD-/PD-L1 are key molecules that are profoundly involved in the inhibitory effects of MDSC on DC function and might be promising tools for clinical application.