来自瘤的细胞外囊泡诱导ER压力,以驱动瘤微环境中的宽容性树突细胞发育
bioRxiv : the preprint server for biology
|February 23, 2026
概括
来自瘤的细胞外囊泡 (EVs) 重新编程树突细胞 (DCs),通过改变其代谢来抑制免疫力. 用抑制剂向PPAR-α可以克服这种抵抗,并增强抗瘤T细胞的反应.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 代谢重编程 代谢重编程
背景情况:
- 免疫检查点阻断的有效性取决于T细胞由树突细胞 (DC) 进行原始化.
- 瘤微环境 (TME) 经常通过代谢变化诱导功能障碍,耐受性DC,阻碍抗瘤免疫力.
- 瘤衍生的细胞外囊泡 (EVs) 在这种DC代谢重编程中的作用尚不清楚.
研究的目的:
- 为了阐明瘤EVs改变DC功能的信号通路.
- 评估针对这些途径的治疗策略,以克服免疫治疗耐药性.
主要方法:
- 工程瘤模型用于EV跟踪和RNA测序.
- 多参数流动细胞计,西式涂抹,qPCR和代谢测试.
- 产生了DC特定的PPAR-α缺乏的小鼠和评估的PPAR-α抑制剂.
主要成果:
- 瘤EVs诱导一种宽容性DC表型 (mregDCs),该表型会损害CD8+T细胞的原始化,并促进调控性T细胞的分化.
- 瘤EV通过PERK和IRE1α激活未折叠蛋白反应 (UPR),从而导致SREBP2和PPAR-α的激活.
- 这导致DC中异常的脂质积累和脂肪酸氧化 (FAO).
- PPAR-α缺乏或抑制逆转了耐受性效应,并在体内增强了抗瘤免疫力.
结论:
- 瘤EVs通过激活UPR通路来促进TME中的mregDC发育和功能.
- 包括FAO在内的异常脂质代谢是TME中DC功能障碍的关键.
- 针对这些代谢途径提供了一种有希望的策略,可以逆转免疫耐受性,并促进CD8+ T细胞的反应.
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