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

被引:45
作者
Asare-Werehene, Meshach [1 ,2 ,3 ]
Communal, Laudine [4 ]
Carmona, Euridice [4 ]
Han, Youngjin [5 ,6 ]
Song, Yong Sang [5 ,6 ]
Burger, Dylan [2 ,3 ,4 ]
Mes-Masson, Anne-Marie [4 ]
Tsang, Benjamin K. [1 ,2 ,3 ,7 ,8 ]
机构
[1] Univ Ottawa, Dept Obstet & Gynecol, Ottawa, ON, Canada
[2] Ottawa Hosp Res Inst, Chron Dis Program, Ottawa, ON, Canada
[3] Univ Montreal, CHUM, Ctr Rech, Montreal, PQ, Canada
[4] Univ Montreal, Inst Canc Montreal, Dept Med, Montreal, PQ, Canada
[5] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea
[6] Seoul Natl Univ, Dept Obstet & Gynecol, Coll Med, Seoul, South Korea
[7] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON, Canada
[8] Univ Ottawa, Ctr Infect Immun & Inflammat, Ottawa, ON, Canada
基金
加拿大健康研究院;
关键词
CHEMOTHERAPY; PROTEIN;
D O I
10.1158/0008-5472.CAN-20-0788
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 IFN gamma, 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. IFN gamma 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 pGSNmediated immune cell dysfunction in ovarian cancer chemoresistance and demonstrate how this dysfunction can be exploited to enhance immunotherapy.
引用
收藏
页码:3959 / 3971
页数:13
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