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IRE1α-XBP1通过调节线粒体活动来控制卵巢癌中的T细胞功能

Minkyung Song^1,2,3, Tito A Sandoval^2,3, Chang-Suk Chae^2,3

¹Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.

|October 12, 2018

概括

卵巢癌会在T细胞中引发细胞内应激,从而激活IRE1α-XBP1通路. 这会损害T细胞代谢和抗瘤功能,但向这种途径可能会恢复免疫反应.

科学领域:

免疫学
癌症生物学
细胞代谢

背景情况:

瘤会产生抑制免疫的微环境, 阻碍T细胞的功能.
瘤中T细胞感知和响应代谢压力的机制尚未完全理解.

研究的目的:

研究卵巢癌如何影响T细胞代谢和抗瘤活性.
阐明细胞内膜网应激和IRE1α-XBP1途径在卵巢癌中T细胞功能障碍中的作用.

主要方法:

来自卵巢癌患者和患者衍生的T细胞的分析.
对未折叠蛋白反应 (UPR) 途径,特别是 IRE1α-XBP1 的研究.
对T细胞代谢,线粒体呼吸和细胞因子产生 (IFNγ) 的测试.
在试验室和活体小鼠模型中对XBP1进行基因操纵.

主要成果:

卵巢癌诱导细胞内膜网应激并激活T细胞中的IRE1α-XBP1,抑制线粒体呼吸和IFNγ产生.
在患者的瘤中,XBP1的上调与T细胞透和IFNGmRNA的减少有关.
恶性炎会损害T细胞的葡萄糖吸收和糖化,从而触发IRE1α- XBP1的激活.
在缺乏葡萄糖的条件下,XBP1调节了谷氨酸的运输,限制了线粒体呼吸.
恢复糖化或抑制IRE1α-XBP1可以增强T细胞的新陈代谢和功能.
在小鼠中,缺乏XBP1的T细胞表现出更好的效应能力,并赋予优异的抗瘤免疫力.

结论:

IRE1α-XBP1通路是卵巢癌微环境中T细胞代谢功能障碍的关键调解者.
向内分泌网膜应激或IRE1α-XBP1信号提供了增强卵巢癌抗瘤免疫力的潜在策略.

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