一致性聚类鉴定两种不同的胰腺导管腺癌免疫亚型

Identification of Two Distinct Immune Subtype of Pancreatic Ductal Adenocarcinoma by Consensus Clustering

摘要: 胰腺导管腺癌早期诊断困难，容易发生肝转移，致死率极高。肿瘤微环境内免疫细胞，纤维细胞与肿瘤细胞之间相互的作用形成了胰腺癌复杂的肿瘤微环境并在其进展过程中发挥了重要作用。免疫治疗在黑色素瘤，结直肠癌，胃癌等晚期肿瘤取得重大突破，显著延长了病人生存周期。然而在胰腺癌中，免疫检查点抑制剂应答率仅为5%，疗效有限。大量研究表明，免疫细胞丰度与病人预后，免疫治疗疗效相关。了解不同胰腺癌免疫亚型之间潜在的调节机制，有助于开发免疫治疗新靶点，指导临床精准用药并预测免疫治疗疗效。本研究通过对145例胰腺癌患者免疫评分，基质评分及肿瘤纯度一致性聚类，鉴定出两种不同的胰腺癌免疫亚型。差异分析，富集分析及蛋白互作网络发现了30个调控肿瘤微环境的hub基因。随后单细胞测序数据分析发现这些hub基因在肿瘤细胞中密度最高，这些基因可能是调控肿瘤细胞与免疫细胞，纤维细胞的关键基因。在形成胰腺癌免疫抑制的肿瘤微环境时发挥了重要作用，可能是胰腺癌免疫治疗的新靶点。

Abstract: Pancreatic ductal adenocarcinoma is an extremely aggressive tumor which susceptible to liver me-tastasis and is difficult to diagnose in the early stages. The interaction between immune cells, fibro-blasts and tumour cells within the tumour microenvironment forms the complex tumour microen-vironment of pancreatic cancer and plays an important role in its progression. Immunotherapy has made significant breakthroughs in advanced tumours such as melanoma, colorectal cancer and gastric cancer, significantly prolonging patient survival days. However, in pancreatic cancer, the re-sponse rate to immune checkpoint inhibitors is only 5%, with limited efficacy. Numerous studies have shown that the abundance of immune cells correlates with patient prognosis and the efficacy of immunotherapy. Understanding the potential regulatory mechanisms between different immune subtypes of pancreatic cancer can help develop new targets for immunotherapy, guide the precise use of clinical drugs and predict the efficacy of immunotherapy. In this study, two distinct immune subtypes of pancreatic cancer were identified by consensus clustering of immune scores, stromal scores and tumour purity in 145 pancreatic cancer patients. Differential analysis, enrichment anal-ysis and protein interaction networks identified 30 hub genes that regulate the tumour microenvi-ronment. Subsequent analysis of single-cell sequencing data revealed that these hub genes were found in the highest densities in tumour cells and that these genes may be key genes regulating tumour cells with immune cells and fibroblasts. They play an important role in shaping the immu-nosuppressive tumour microenvironment in pancreatic cancer and may be new targets for immu-notherapy of pancreatic cancer.