Ewing Sarcoma-Derived Extracellular Vesicles Impair Dendritic Cell Maturation and Function
Hendrik Gassmann,
Kira Schneider,
Valentina Evdokimova,
Peter Ruzanov,
Sebastian J. Schober,
Busheng Xue,
Kristina von Heyking,
Melanie Thiede,
Guenther H. S. Richter,
Michael W. Pfaffl,
Elfriede Noessner,
Lincoln D. Stein,
Poul H. Sorensen,
Stefan E. G. Burdach,
Uwe Thiel
Affiliations
Hendrik Gassmann
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Kira Schneider
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Valentina Evdokimova
Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada
Peter Ruzanov
Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada
Sebastian J. Schober
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Busheng Xue
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Kristina von Heyking
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Melanie Thiede
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Guenther H. S. Richter
Division of Oncology and Hematology, Department of Pediatrics, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
Michael W. Pfaffl
Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany
Elfriede Noessner
Immunoanalytics Research Group—Tissue Control of Immunocytes, Helmholtz Center, 81377 Munich, Germany
Lincoln D. Stein
Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada
Poul H. Sorensen
Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada
Stefan E. G. Burdach
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Uwe Thiel
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
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.
