| Summary: | Extracellular vesicles (EV) and their tumor-supporting cargos provide a promising translational potential in liquid biopsies for risk assessment of epithelial ovarian cancer (EOC) patients frequently relapsing, despite initial complete therapy responses. As the immune checkpoint molecule HLA-G, which is operative in immune-escape, can be released by EV, we evaluate the abundance of EV and its vesicular-bound amount of HLA-G (HLA-G<sub>EV</sub>) as a biomarker in EOC. After enrichment of EV from plasma samples, we determined the EV particle number and amount of HLA-G<sub>EV</sub> by nanoparticle tracking analysis or ELISA. The association of results with the clinical status/outcome revealed that both, EV particle number and HLA-G<sub>EV</sub> were significantly elevated in EOC patients, compared to healthy females. However, elevated levels of HLA-G<sub>EV</sub>, but not EV numbers, were exclusively associated with a disadvantageous clinical status/outcome, including residual tumor, presence of circulating tumor cells, and disease progression. High HLA-G<sub>EV</sub> status was an independent predictor of progression, besides residual tumor burden and platinum-sensitivity. Especially among patients without residual tumor burden or with platinum-sensitivity, HLA-G<sub>EV</sub> identified patients with high risk of progression. Thus, this study highlights HLA-G<sub>EV</sub> as a potential novel biomarker for risk assessment of EOC patients with a rather beneficial prognosis defined by platinum-sensitivity or lack of residual tumor burden.
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