空间分离的APOE+巨细胞限制了清细胞细胞癌中免疫疗法的有效性
Qintao Ge1,2, Jialin Meng3,4,5, Zhongyuan Wang1,2
1Department of Urology, Fudan University Shanghai Cancer Center; Center; Department of Oncology, Shanghai Medical College; Qingdao Institute of Life Sciences, Fudan University, Shanghai, 200032, P.R. China.
Theranostics
|April 30, 2025
概括
转移性清细胞细胞癌 (ccRCC) 中的免疫检查点阻塞 (ICB) 抵抗与抑制抗瘤免疫力的APOE+巨细胞有关. 准这些巨细胞可能会提高ICB治疗的疗效.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 癌症研究 癌症研究
背景情况:
- 免疫疗法对转移性清晰细胞脏细胞癌 (ccRCC) 有希望.
- 瘤微环境 (TME) 内的免疫抵抗限制了免疫治疗的有效性和耐久性.
- 了解ccRCC中的免疫耐受机制对于改善治疗结果至关重要.
研究的目的:
- 研究用免疫检查点阻塞 (ICB) 治疗的ccRCC中免疫抵抗的机制.
- 识别关键的细胞组件和信号通路,有助于在ccRCC中产生ICB耐药性.
- 探索针对ccRCC中的免疫抵抗的潜在治疗策略.
主要方法:
- 分析了2000多个样本,包括230名用ICB治疗的晚期ccRCC患者.
- 由ICB响应分类的瘤区域的单细胞RNA测序.
- 多重体免疫光和空间分析以评估TME组成和巨细胞异质性.
- 在体外实验中评估分泌蛋白1 (SPP1) 在ccRCC细胞行为和巨细胞两极分化中的作用.
主要成果:
- 在ICB抗性ccRCC中发现了升高的Apolipoprotein E (APOE) +巨细胞,与更差的预后和降低的ICB反应相关.
- 增加的CCAAT增强剂结合蛋白Delta (CEBPD) 表达与免疫抑制途径有关,阻碍T细胞功能.
- 来自瘤的SPP1促进了ccRCC细胞的增殖和迁移,并将巨细胞招募/极化为一种免疫抑制的APOE+ M2类表型.
- 这些APOE+巨细胞产生TGF-β,抑制抗瘤T细胞活性,并促进免疫抵抗.
结论:
- 在ccRCC中,APOE+巨细胞在促进免疫抑制和ICB抵抗方面发挥着至关重要的作用.
- 这些巨细胞有助于T细胞耗尽,并通过TGF-β信号传递产生免疫抑制的TME.
- 向APOE+巨细胞,可能与ICB结合,是提高ccRCC治疗疗效的有希望的策略.
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