Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis
Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis
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DOI：
10.1080/2162402x.2015.1069938
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Agostinis, Patrizia
中科院分区：
文献类型：
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作者：
Garg, Abhishek D.;De Ruysscher, Dirk;Agostinis, Patrizia
癌细胞-免疫细胞界面在形成肿瘤发生/抗癌免疫治疗中的新兴作用增加了识别预后生物标志物的需求。尽管如此，我们的主要目的是确定乳腺癌、肺癌和卵巢癌中与改善患者生存相关的免疫原性细胞死亡（ICD）衍生的多基因特征。为此，我们通过一项涉及3，983例患者（“发现”数据集）的大规模荟萃分析，分析了33个临床前验证的ICD参数的差异基因表达的预后影响，这些患者包括肺（1，432）、乳腺（1，115）和卵巢（1，436）恶性肿瘤。主要结果也在由818例相同癌症类型（即285例乳腺癌/274例肺癌/259例卵巢癌）患者组成的“验证”数据集中得到证实。ICD相关参数表现出高度聚集性和很大程度上的癌症类型特异性预后影响。有趣的是，我们描绘了ICD衍生的共识-元基因签名，这些签名表现出积极的预后影响，无论是癌症类型无关的还是特异性的。重要的是，大多数这些ICD衍生的共识-元基因（作为吸引子-元基因，从而）“吸引”高度共表达的基因或会聚-元基因集。这些会聚-多基因在相应的癌症类型中也表现出积极的预后影响。值得注意的是，我们发现癌症类型独立的共识元基因充当癌症特异性会聚元基因的“吸引子”。这再次证实了癌症的免疫学预后前景倾向于在癌症非依赖性和癌症类型特异性基因特征之间分离。此外，这种预后景观主要由经典的T细胞活性/浸润/功能相关的生物标志物主导。有趣的是，每种癌症类型往往与代表特定T细胞活性或功能的生物标志物相关，而不是泛T细胞生物标志物。因此，我们的分析证实ICD可以作为发现新的预后多基因的平台。
The emerging role of the cancer cell-immune cell interface in shaping tumorigenesis/anticancer immunotherapy has increased the need to identify prognostic biomarkers. Henceforth, our primary aim was to identify the immunogenic cell death (ICD)-derived metagene signatures in breast, lung and ovarian cancer that associate with improved patient survival. To this end, we analyzed the prognostic impact of differential gene-expression of 33 pre-clinically-validated ICD-parameters through a large-scale meta-analysis involving 3,983 patients ('discovery' dataset) across lung (1,432), breast (1,115) and ovarian (1,436) malignancies. The main results were also substantiated in 'validation' datasets consisting of 818 patients of same cancer-types (i.e. 285 breast/274 lung/259 ovarian). The ICD-associated parameters exhibited a highly-clustered and largely cancer type-specific prognostic impact. Interestingly, we delineated ICD-derived consensus-metagene signatures that exhibited a positive prognostic impact that was either cancer type-independent or specific. Importantly, most of these ICD-derived consensus-metagenes (acted as attractor-metagenes and thereby) 'attracted' highly co-expressing sets of genes or convergent-metagenes. These convergent-metagenes also exhibited positive prognostic impact in respective cancer types. Remarkably, we found that the cancer type-independent consensus-metagene acted as an 'attractor' for cancer-specific convergent-metagenes. This reaffirms that the immunological prognostic landscape of cancer tends to segregate between cancer-independent and cancer-type specific gene signatures. Moreover, this prognostic landscape was largely dominated by the classical T cell activity/infiltration/function-related biomarkers. Interestingly, each cancer type tended to associate with biomarkers representing a specific T cell activity or function rather than pan-T cell biomarkers. Thus, our analysis confirms that ICD can serve as a platform for discovery of novel prognostic metagenes.