Immunological network analysis in HPV associated head and neck squamous cancer and implications for disease prognosis
Immunological network analysis in HPV associated head and neck squamous cancer and implications for disease prognosis
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HPV相关头颈鳞癌的免疫网络分析及其对疾病预后的影响
DOI：
10.1016/j.molimm.2018.02.005
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发表时间：
2018-04-01
影响因子：
3.6
通讯作者：
Zhang, Fengmin
中科院分区：
文献类型：
--
作者：
Chen, Xiaohang;Yan, Bingqing;Zhang, Fengmin
人乳头瘤病毒阳性(HPV+)头颈部鳞状细胞癌(HNSCC)预后好于HPV阴性(HPV-)头颈部鳞状细胞癌。这种差异可能部分是由于HPV+HNSCC肿瘤微环境中免疫活性增强所致。为了表征HPV+和HPV-HNSCC肿瘤在免疫激活方面的差异，我们基于癌症基因组图谱(TCGA)的mRNA表达数据识别和注释了差异表达的基因。利用单样本基因集浓缩分析和条件互信息构建免疫细胞与细胞因子之间的免疫网络。多因素COX回归分析确定免疫微环境特征对预后的预测价值。共对1673个差异表达基因进行了功能注释。我们发现，在HPV+HNSCC中上调的基因在免疫相关过程中得到丰富。并通过基因集浓缩分析对上调的基因集进行验证。与HPV-HNSCC相比，HPV+HNSCC的微环境表现出更多的B细胞和T细胞，以及更少的中性粒细胞。这些发现得到了基因表达总览(GEO)数据库中两个独立的数据集的验证。进一步的T细胞亚群分析显示，HPV+HNSCC以细胞毒性T细胞亚群为主。此外，HPV+HNSCC中M1/M2巨噬细胞比例较高。这些免疫细胞的渗透与差异表达的细胞因子相关基因有关。B细胞和CD8+T细胞的浸润增强是HPV+HNSCC的独立保护因素，而中性粒细胞的高渗透则是HPV+HNSCC患者的危险增加因素。建立了HPV+HNSCC的免疫网络模型，总结了我们的研究结果。
Human papillomavirus-positive (HPV +) head and neck squamous cell cancer (HNSCC) exhibits a better prognosis than HPV-negative (HPV -) HNSCC. This difference may in part be due to enhanced immune activation in the HPV + HNSCC tumor microenvironment. To characterize differences in immune activation between HPV + and HPV - HNSCC tumors, we identified and annotated differentially expressed genes based upon mRNA expression data from The Cancer Genome Atlas (TCGA). Immune network between immune cells and cytokines was constructed by using single sample Gene Set Enrichment Analysis and conditional mutual information. Multivariate Cox regression analysis was used to determine the prognostic value of immune microenvironment characterization. A total of 1673 differentially expressed genes were functionally annotated. We found that genes upregulated in HPV + HNSCC are enriched in immune-associated processes. And the up-regulated gene sets were validated by Gene Set Enrichment Analysis. The microenvironment of HPV + HNSCC exhibited greater numbers of infiltrating B and T cells and fewer neutrophils than HPV - HNSCC. These findings were validated by two independent datasets in the Gene Expression Omnibus (GEO) database. Further analyses of T cell subtypes revealed that cytotoxic T cell subtypes predominated in HPV + HNSCC. In addition, the ratio of M1/M2 macrophages was much higher in HPV + HNSCC. The infiltration of these immune cells was correlated with differentially expressed cytokine-associated genes. Enhanced infiltration of B cells and CD8 + T cells were identified as independent protective factors, while high neutrophil infiltration was a risk enhancing factor for HPV + HNSCC patients. A schematic model of immunological network was established for HPV + HNSCC to summarize our findings.