Plasma gelsolin inhibits CD8+ T cell function and regulates glutathione production to confer chemoresistance in ovarian cancer.

Although initial treatment of ovarian cancer (OVCA) is successful, tumors typically relapse and become resistant to treatment. Due to poor infiltration of effector T cells, patients are mostly unresponsive to immunotherapy. Plasma gelsolin (pGSN) is transported by exosomes (sEV) and plays a key role in OVCA chemoresistance, yet little is known about its role in immunosurveillance. Here we report the immunomodulatory roles of sEV-pGSN in OVCA 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 cisplatin (CDDP)-induced apoptosis. In chemoresistant conditions, increased secretion of sEV-pGSN by OVCA cells induced apoptosis in CD8+ T cells. IFNγ secretion was therefore reduced, resulting in high GSH production and resistance to CDDP-induced death in OVCA cells. These findings support our hypothesis that sEV-pGSN attenuates immunosurveillance and regulates GSH biosynthesis, a phenomenon that contributes to chemoresistance in OVCA.