Increased immune gene expression and immune cell infiltration in high-grade astrocytoma distinguish long-term from short-term survivors.
Increased immune gene expression and immune cell infiltration in high-grade astrocytoma distinguish long-term from short-term survivors.
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DOI：
10.4049/jimmunol.1103373
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发表时间：
2012-08-15
期刊：
影响因子：
--
通讯作者：
Foreman NK
中科院分区：
文献类型：
--
作者：
Donson AM;Birks DK;Schittone SA;Kleinschmidt-DeMasters BK;Sun DY;Hemenway MF;Handler MH;Waziri AE;Wang M;Foreman NK
大多数高级别星形细胞瘤（HGA）患者的生存率非常低，只有少数患者长期存活。更好地了解与HGA长期生存相关的生物学因素将有助于开发更有效的治疗和生存预测。与长期生存相关的因素尚未使用无偏倚的全基因组表达分析进行广泛研究。在本研究中，从长期生存者的HGA基因表达微阵列配置文件进行了查询，发现生存相关的生物因素。本体分析显示，免疫功能相关基因表达的增加是与生存期延长呈正相关的主要生物学因素。一个值得注意的T细胞签名存在于这个预后免疫基因集。使用免疫细胞特异性基因分类器，T细胞和髓系相关基因都显示出在长期与短期存活者的HGA中富集。免疫功能和细胞特异性基因与存活率的关联在一个更大的公开的胶质母细胞瘤基因表达微阵列数据集中被独立地证实。组织学被用来验证在一个更大的队列的长期生存的HGA的微阵列分析的结果。多变量分析表明，增加免疫细胞浸润是一个重要的独立变量，有助于延长生存期，是Karnofsky/Lansky性能评分。这些数据提供了预后性抗肿瘤适应性免疫应答的证据，并为HGA免疫治疗的未来发展提供了理论基础。
Survival in the majority of high grade astrocytoma (HGA) patients is very poor, with only a rare population of long-term survivors. A better understanding of the biological factors associated with long-term survival in HGA would aid development of more effective therapy and survival prediction. Factors associated with long-term survival have not been extensively studied using unbiased genome-wide expression analyses. In the present study, gene expression microarray profiles of HGA from long-term survivors were interrogated for discovery of survival-associated biological factors. Ontology analyses revealed that increased expression of immune function-related genes was the predominant biological factor that positively correlated with longer survival. A notable T-cell signature was present within this prognostic immune gene-set. Using immune cell-specific gene classifiers, both T-cell and myeloid linage-associated genes were shown to be enriched in HGA from long versus short-term survivors. Association of immune function and cell-specific genes with survival was confirmed independently in a larger publicly available glioblastoma gene expression microarray dataset. Histology was used to validate the results of microarray analyses in a larger cohort of long-term survivors of HGA. Multivariate analyses demonstrated that increased immune cell infiltration was a significant independent variable contributing to longer survival, as was Karnofsky/Lansky performance score. These data provide evidence of a prognostic anti-tumor adaptive immune response and rationale for future development of immunotherapy in HGA.
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