Ewing Sarcoma-Derived Extracellular Vesicles Impair Dendritic Cell Maturation and Function

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 8; p. 2081
• Main Authors: Gassmann, Hendrik, Schneider, Kira, Evdokimova, Valentina, Ruzanov, Peter, Schober, Sebastian J., Xue, Busheng, von Heyking, Kristina, Thiede, Melanie, Richter, Guenther H. S., Pfaffl, Michael W., Noessner, Elfriede, Stein, Lincoln D., Sorensen, Poul H., Burdach, Stefan E. G., Thiel, Uwe
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 13-08-2021; MDPI
• Subjects: Antibodies; Antigen-presenting cells; Antigens; Bone cancer; Cancer; CD14 antigen; CD4 antigen; CD63 antigen; CD8 antigen; CD80 antigen; CD81 antigen; CD86 antigen; Cell differentiation; Cell growth; Cell proliferation; Cytokines; Cytotoxicity; Dendritic cells; Ewing sarcoma; Ewing's sarcoma; Ewings sarcoma; Extracellular vesicles; Flow cytometry; Gene expression; Histocompatibility antigen HLA; immunosuppression; Inflammation; Interleukin 10; Interleukin 6; Interleukin 8; Lymphocytes; Lymphocytes T; Metastases; myeloid cells; Pediatrics; Phenotypes; Plasma; γ-Interferon; United States > US; Switzerland; Germany
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10082081

Ewing sarcoma (EwS) is an aggressive pediatric cancer of bone and soft tissues characterized by scant T cell infiltration and predominance of immunosuppressive myeloid cells. Given the important roles of extracellular vesicles (EVs) in cancer-host crosstalk, we hypothesized that EVs secreted by EwS tumors target myeloid cells and promote immunosuppressive phenotypes. Here, EVs were purified from EwS and fibroblast cell lines and exhibited characteristics of small EVs, including size (100–170 nm) and exosome markers CD63, CD81, and TSG101. Treatment of healthy donor-derived CD33+ and CD14+ myeloid cells with EwS EVs but not with fibroblast EVs induced pro-inflammatory cytokine release, including IL-6, IL-8, and TNF. Furthermore, EwS EVs impaired differentiation of these cells towards monocytic-derived dendritic cells (moDCs), as evidenced by reduced expression of co-stimulatory molecules CD80, CD86 and HLA-DR. Whole transcriptome analysis revealed activation of gene expression programs associated with immunosuppressive phenotypes and pro-inflammatory responses. Functionally, moDCs differentiated in the presence of EwS EVs inhibited CD4+ and CD8+ T cell proliferation as well as IFNγ release, while inducing secretion of IL-10 and IL-6. Therefore, EwS EVs may promote a local and systemic pro-inflammatory environment and weaken adaptive immunity by impairing the differentiation and function of antigen-presenting cells.