Plasma Gelsolin Inhibits CD8+ T-cell Function and Regulates Glutathione Production to Confer Chemoresistance in Ovarian Cancer
Plasma Gelsolin Inhibits CD8+ T-cell Function and Regulates Glutathione Production to Confer Chemoresistance in Ovarian Cancer
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DOI：
10.1158/0008-5472.can-20-0788
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发表时间：
2020-09-15
期刊：
影响因子：
11.2
通讯作者：
Tsang, Benjamin K.
中科院分区：
文献类型：
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作者：
Asare-Werehene, Meshach;Communal, Laudine;Tsang, Benjamin K.
虽然卵巢癌的初始治疗是成功的，但肿瘤通常会复发并对治疗产生耐药性。由于效应T细胞的浸润较差，患者大多对免疫治疗无反应。血浆凝溶胶蛋白（plasma gelsolin，pGSN）是由外泌体（small extracellular vesicle，sEV）转运的，在卵巢癌化疗耐药中起关键作用，但其在免疫监视中的作用尚不清楚。在这里，我们报告了sEV-pGSN在卵巢癌化疗耐药中的免疫调节作用。在化学敏感的条件下，sEV-pGSN的分泌较低，允许最佳的CD 8（+）T细胞功能。这导致IFN γ的T细胞分泌增加，从而减少细胞内谷胱甘肽（GSH）的产生并使化学敏感细胞对顺式二胺二氯铂（CDDP）诱导的凋亡敏感。在化疗耐药条件下，卵巢癌细胞分泌的sEV-pGSN增加诱导CD 8（+）T细胞凋亡。因此，IFN γ分泌减少，导致卵巢癌细胞产生高GSH并对CDDP诱导的死亡产生抗性。这些研究结果支持我们的假设，sEV-pGSN减弱免疫监视和调节GSH的生物合成，一种现象，有助于卵巢cancer.Significance化疗耐药：这些研究结果提供了新的见解pGSN介导的免疫细胞功能障碍卵巢癌化疗耐药，并证明如何利用这种功能障碍，以提高免疫治疗。
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.