Exosomes isolated from plasma of glioma patients enrolled in a vaccination trial reflect antitumor immune activity and might predict survival
Exosomes isolated from plasma of glioma patients enrolled in a vaccination trial reflect antitumor immune activity and might predict survival
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DOI：
10.1080/2162402x.2015.1008347
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发表时间：
2015-06-01
期刊：
影响因子：
7.2
通讯作者：
Whiteside, Theresa L.
中科院分区：
文献类型：
--
作者：
Muller, Laurent;Muller-Haegele, Sylvia;Whiteside, Theresa L.
胶质瘤患者血浆中的外泌体有望作为预后的生物标志物。我们的目的是确定总外泌体蛋白和mRNA表达水平的变化是否可以作为接受抗肿瘤疫苗的胶质瘤患者的免疫和临床反应的替代标志物。从参加抗肿瘤疫苗I/II期试验的20/22例患者的疫苗接种前/接种后血浆标本中分离外来体。分析外泌体蛋白含量，并通过qRT-PCR同时评估24个基因的mRNA表达水平。使用斯皮尔曼等级统计和风险比（HR），将接种前至接种后外泌体蛋白和Ct值的变化与免疫学和临床应答以及存活率相关。外泌体蛋白水平与诊断时的WHO肿瘤分级正相关（p < 0.0043）。与接种前相比，接种后外泌体级分中的蛋白质水平较低。治疗后肿瘤大小的增加与胶质母细胞瘤中外泌体蛋白的升高相关，但在间变性星形细胞瘤（AA）中并不总是如此。只有IL-8、TIMP-1、TGF-β和ZAP 70的外来体Ct值是显著的（p < 0.04至p < 0.001）。IL-8和TGF-β mRNA的Ct与疫苗后对胶质瘤抗原的免疫应答呈正相关，而TIMP-1 mRNA的Ct与IL-8和TGF-β的Ct呈负相关。只有IL-8的Ct与OS和疾病进展时间（TTP）弱相关。在存活时间最长的AA患者的疫苗后外泌体中，PD-1的mRNA持续升高。血浆外泌体中免疫相关基因的蛋白质和mRNA表达水平可用于评估胶质瘤患者对疫苗接种治疗的反应。
Exosomes in plasma of glioma patients hold promise as biomarkers of prognosis. We aimed to determine whether changes in total exosomal protein and mRNA expression levels could serve as surrogate markers of immunological and clinical responses in glioma patients receiving antitumor vaccines. Exosomes were isolated from pre/post-vaccine plasma specimens in 20/22 patients enrolled in a phase I/II trial with the antitumor vaccine. Exosomal protein content was analyzed and mRNA expression levels for 24 genes were simultaneously assessed by qRT-PCR. Pre- to post-vaccination changes in exosomal protein and Ct values were correlated with immunological and clinical responses and survival using Spearman rank statistics and hazard ratios (HR). Exosomal protein levels positively correlated (p < 0.0043) with the WHO tumor grade at diagnosis. Protein levels were lower in post- vs. pre-vaccination exosome fractions. Post-therapy increases in tumor size were associated with elevations in exosome proteins in glioblastoma but not always in anaplastic astrocytoma (AA). Only exosomal Ct values for IL-8, TIMP-1, TGF- and ZAP70 were significant (p < 0.04 to p < 0.001). The Ct for IL-8 and TGF- mRNA positively correlated with post-vaccine immunologic responses to glioma antigens, while Ct for TIMP-1 mRNA was negatively correlated to Ct for IL-8 and TGF-. Only Ct for IL-8 weakly correlated with OS and time to progression (TTP). In post-vaccine exosomes of the longest surviving patient with AA, mRNA for PD-1 was persistently elevated. Protein and mRNA expression levels for immune-related genes in plasma exosomes were useful in evaluating glioma patients' response to vaccination therapy.