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

Cells

Poul H. Sorensen¹  Stefan E. G. Burdach²  Sebastian J. Schober²  Kira Schneider²  Kristina von Heyking²  Melanie Thiede²  Busheng Xue²  Uwe Thiel²  Hendrik Gassmann²  Michael W. Pfaffl³  Guenther H. S. Richter⁴  Elfriede Noessner⁵  Valentina Evdokimova⁶  Lincoln D. Stein⁶  Peter Ruzanov⁶ 

[1] Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada;Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany;Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany;Division of Oncology and Hematology, Department of Pediatrics, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany;Immunoanalytics Research Group—Tissue Control of Immunocytes, Helmholtz Center, 81377 Munich, Germany;Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada;

关键词: myeloid cells;    dendritic cells;    Ewing sarcoma;    extracellular vesicles;    inflammation;    immunosuppression;   

DOI  :  10.3390/cells10082081

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown