Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant tumor. The immune profile of PDAC and the immunologic milieu of its tumor microenvironment (TME) are unique; however, the mechanism of how the TME engineers the carcinogenesis of PDAC is not fully understood. This study is aimed at better understanding the relationship between the immune infiltration of the TME and gene expression and identifying potential prognostic and immunotherapeutic biomarkers for PDAC. Analysis of data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases identified differentially expressed genes (DEGs), including 159 upregulated and 53 downregulated genes. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment were performed and showed that the DEGs were mainly enriched for the PI3K-Akt signaling pathway and extracellular matrix organization. We used the cytoHubba plugin of Cytoscape to screen out the most significant ten hub genes by four different models (Degree, MCC, DMNC, and MNC). The expression and clinical relevance of these ten hub genes were validated using Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas, respectively. High expression of nine of the hub genes was positively correlated with poor prognosis. Finally, the relationship between these hub genes and tumor immunity was analyzed using the Tumor Immune Estimation Resource. We found that the expression of SPARC, COL6A3, and FBN1 correlated positively with infiltration levels of six immune cells in the tumors. In addition, these three genes had a strong coexpression relationship with the immune checkpoints. In conclusion, our results suggest that nine upregulated biomarkers are related to poor prognosis in PDAC and may serve as potential prognostic biomarkers for PDAC therapy. Furthermore, SPARC, COL6A3, and FBN1 play an important role in tumor-related immune infiltration and may be ideal targets for immune therapy against PDAC.

中文翻译：

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胰腺导管腺癌关键预后生物标志物的鉴定及其与免疫浸润的关系。

胰腺导管腺癌（PDAC）是一种极为恶性的肿瘤。PDAC的免疫特征及其肿瘤微环境（TME）的免疫环境是独特的；但是，TME如何工程化PDAC致癌的机制尚不完全清楚。这项研究旨在更好地了解TME的免疫浸润与基因表达之间的关系，并确定PDAC的潜在预后和免疫治疗生物标志物。来自癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）的数据分析确定了差异表达基因（DEG），包括159个上调的基因和5​​3个下调的基因。进行了基因本体论分析和《京都议定书》的基因与基因组富集，结果表明DEGs主要用于PI3K-Akt信号通路和细胞外基质的组织富集。我们使用Cytoscape的cytoHubba插件通过四种不同的模型（Degree，MCC，DMNC和MNC）筛选出最重要的十个中心基因。分别使用基因表达谱交互式分析（GEPIA）和人类蛋白质图谱验证了这10个中枢基因的表达和临床相关性。9个中枢基因的高表达与不良预后正相关。最后，使用肿瘤免疫估计资源分析了这些中枢基因与肿瘤免疫之间的关系。我们发现SPARC，COL6A3，FBN1和FBN1与肿瘤中六个免疫细胞的浸润水平呈正相关。另外，这三个基因与免疫检查点具有很强的共表达关系。总之，我们的结果表明9种上调的生物标志物与PDAC的预后不良有关，并可作为PDAC治疗的潜在预后生物标志物。此外，SPARC，COL6A3和FBN1在肿瘤相关的免疫浸润中起重要作用，并且可能是针对PDAC进行免疫治疗的理想靶标。