Plasma Gelsolin Inhibits CD8(+) T-cell Function and Regulates Glutathione Production to Confer Chemoresistance in Ovarian Cancer.

Although initial treatment of ovarian cancer is successful, tumors typically relapse and become resistant to treatment. Because of poor infiltration of effector T cells, patients are mostly unresponsive to immunotherapy. Plasma gelsolin (pGSN) is transported by exosomes (small extracellular vesicle, sEV) and plays a key role in ovarian cancer chemoresistance, yet little is known about its role in immunosurveillance. Here, we report the immunomodulatory roles of sEV-pGSN in ovarian cancer chemoresistance. In chemosensitive conditions, secretion of sEV-pGSN was low, allowing for optimal CD8+ T-cell function. This resulted in increased T-cell secretion of IFNγ, which reduced intracellular glutathione (GSH) production and sensitized chemosensitive cells to cis-diaminedichloroplatinum (CDDP)-induced apoptosis. In chemoresistant conditions, increased secretion of sEV-pGSN by ovarian cancer cells induced apoptosis in CD8+ T cells. IFNγ secretion was therefore reduced, resulting in high GSH production and resistance to CDDP-induced death in ovarian cancer cells. These findings support our hypothesis that sEV-pGSN attenuates immunosurveillance and regulates GSH biosynthesis, a phenomenon that contributes to chemoresistance in ovarian cancer. SIGNIFICANCE: These findings provide new insight into pGSN-mediated immune cell dysfunction in ovarian cancer chemoresistance and demonstrate how this dysfunction can be exploited to enhance immunotherapy.

Asare-Werehene M ，Communal L ，Carmona E ，Han Y ，Song YS ，Burger D ，Mes-Masson AM ，Tsang BK ... -  《-》

Plasma Gelsolin Inhibits Natural Killer Cell Function and Confers Chemoresistance in Epithelial Ovarian Cancer.

Onuma T ，Asare-Werehene M ，Fujita Y ，Yoshida Y ，Tsang BK ... -  《Cells》

Exosomal Plasma Gelsolin Is an Immunosuppressive Mediator in the Ovarian Tumor Microenvironment and a Determinant of Chemoresistance.

Onuma T ，Asare-Werehene M ，Yoshida Y ，Tsang BK ... -  《Cells》

The exosome-mediated autocrine and paracrine actions of plasma gelsolin in ovarian cancer chemoresistance.

Asare-Werehene M ，Nakka K ，Reunov A ，Chiu CT ，Lee WT ，Abedini MR ，Wang PW ，Shieh DB ，Dilworth FJ ，Carmona E ，Le T ，Mes-Masson AM ，Burger D ，Tsang BK ... -  《-》

The regulation of plasma gelsolin by DNA methylation in ovarian cancer chemo-resistance.

Manzoor HB ，Asare-Werehene M ，Pereira SD ，Satyamoorthy K ，Tsang BK ... -  《Journal of Ovarian Research》