Development and Validation of a Combined Hypoxia and Immune Prognostic Classifier for Head and Neck Cancer
Development and Validation of a Combined Hypoxia and Immune Prognostic Classifier for Head and Neck Cancer
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DOI：
10.1158/1078-0432.ccr-18-3314
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发表时间：
2019-09-01
影响因子：
11.5
通讯作者：
Mehanna, Hisham
中科院分区：
文献类型：
--
作者：
Brooks, Jill M.;Menezes, Albert N.;Mehanna, Hisham
目的：肿瘤内缺氧和免疫与各种肿瘤患者的预后相关。然而，由于缺乏经过验证的生物标志物，这些因素目前没有被考虑用于头颈癌（HNC）的治疗选择。在这里，我们试图开发一个缺氧免疫分类与潜在的应用在病人的诊断和预测的反应，以靶向therapeutic.Experimental设计：一个54基因的缺氧免疫签名的基础上构建的文献综述。使用The Cancer Genome Atlas（TCGA）HNC数据集（n = 275）在计算机中分析基因表达，并使用两个独立的群组（n = 130和123）进行验证。使用IHC来研究简化的蛋白质签名的效用。采用多重免疫荧光染色法检测缺氧和免疫标志物的空间分布。（开发队列）确定了三个具有不同缺氧免疫表型和生存特征的患者亚组：缺氧（低）/免疫（高）、缺氧（高）/免疫（低）和混合组的5年总生存率（OS）分别为71%、51%和49%（P = 0.0015）。缺氧免疫基因标记的预后相关性在两个独立的验证队列中重复。多变量分析显示，只有PDL 1和肿瘤内CD 3蛋白表达与OS改善相关。缺氧（低）/免疫（高）和缺氧（高）/免疫（低）肿瘤分别在“发炎”和“免疫沙漠”微环境中过度表现。多重染色显示CA-IX表达与肿瘤内CD 3（+）T细胞的流行率呈负相关（r = -0.5464; P = 0.0377），进一步证实了基于转录的分类。我们开发并验证了一个缺氧免疫预后转录分类器，其可能具有临床应用以指导用于治疗HNC的低氧修饰和靶向免疫疗法的使用。
Purpose: Intratumoral hypoxia and immunity have been correlated with patient outcome in various tumor settings. However, these factors are not currently considered for treatment selection in head and neck cancer (HNC) due to lack of validated biomarkers. Here we sought to develop a hypoxiaimmune classifier with potential application in patient prognostication and prediction of response to targeted therapy.Experimental Design: A 54-gene hypoxia-immune signature was constructed on the basis of literature review. Gene expression was analyzed in silico using the The Cancer Genome Atlas (TCGA) HNC dataset (n = 275) and validated using two independent cohorts (n = 130 and 123). IHC was used to investigate the utility of a simplified protein signature. The spatial distribution of hypoxia and immune markers was examined using multiplex immunofluorescence staining.Results: Unsupervised hierarchical clustering of TCGA dataset (development cohort) identified three patient subgroups with distinct hypoxia-immune phenotypes and survival profiles: hypoxia(low)/immune(high), hypoxia(high)/immune(low), and mixed, with 5-year overall survival (OS) rates of 71%, 51%, and 49%, respectively (P = 0.0015). The prognostic relevance of the hypoxia-immune gene signature was replicated in two independent validation cohorts. Only PDL1 and intratumoral CD3 protein expression were associated with improved OS on multivariate analysis. Hypoxia(low)/immune(high) and hypoxia(high)/immune(low) tumors were over-represented in "inflamed" and "immune-desert" microenvironmental profiles, respectively. Multiplex staining demonstrated an inverse correlation between CA-IX expression and prevalence of intratumoral CD3(+) T cells (r = -0.5464; P = 0.0377), further corroborating the transcription-based classification.Conclusions: We developed and validated a hypoxiaimmune prognostic transcriptional classifier, which may have clinical application to guide the use of hypoxia modification and targeted immunotherapies for the treatment of HNC.