The Second School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China.
Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China.
Int J Mol Sci. 2023 Aug 14;24(16):12787. doi: 10.3390/ijms241612787.
Tumor-associated macrophages M2 (TAM2), which are highly prevalent infiltrating immune cells in the stroma of pancreatic cancer (PC), have been found to induce an immunosuppressive tumor microenvironment, thus enhancing tumor initiation and progression. However, the immune therapy response and prognostic significance of regulatory genes associated with TAM2 in PC are currently unknown. Based on TCGA transcriptomic data and single-cell sequencing data from the GEO database, we identified TAM2-driven genes using the WGCNA algorithm. Molecular subtypes based on TAM2-driven genes were clustered using the ConsensusClusterPlus algorithm. The study constructed a prognostic model based on TAM2-driven genes through Lasso-COX regression analysis. A total of 178 samples obtained by accessing TCGA were accurately categorized into two molecular subtypes, including the high-TAM2 infiltration (HMI) cluster and the low-TAM2 infiltration (LMI) cluster. The HMI cluster exhibits a poor prognosis, a malignant tumor phenotype, immune-suppressive immune cell infiltration, resistance to immunotherapy, and a high number of genetic mutations, while the LMI cluster is the opposite. The prognostic model composed of six hub genes from TAM2-driven genes exhibits a high degree of accuracy in predicting the prognosis of patients with PC and serves as an independent risk factor. The induction of TAM2 was employed as a means of verifying these six gene expressions, revealing the significant up-regulation of BCAT1, BST2, and MERTK in TAM2 cells. In summary, the immunophenotype and prognostic model based on TAM2-driven genes offers a foundation for the clinical management of PC. The core TAM2-driven genes, including BCAT1, BST2, and MERTK, are involved in regulating tumor progression and TAM2 polarization, which are potential targets for PC therapy.
肿瘤相关巨噬细胞 M2（TAM2）是胰腺癌（PC）基质中高度浸润的免疫细胞，已被发现能诱导免疫抑制性肿瘤微环境，从而增强肿瘤的起始和进展。然而，与 PC 中 TAM2 相关的调节基因的免疫治疗反应和预后意义目前尚不清楚。基于 TCGA 转录组数据和 GEO 数据库的单细胞测序数据，我们使用 WGCNA 算法鉴定了 TAM2 驱动基因。使用 ConsensusClusterPlus 算法根据 TAM2 驱动基因聚类分子亚型。通过 Lasso-COX 回归分析构建基于 TAM2 驱动基因的预后模型。通过访问 TCGA 获得的 178 个样本被准确地分为两个分子亚型，包括高 TAM2 浸润（HMI）簇和低 TAM2 浸润（LMI）簇。HMI 簇表现出预后不良、恶性肿瘤表型、免疫抑制性免疫细胞浸润、对免疫治疗的耐药性和大量基因突变，而 LMI 簇则相反。由 TAM2 驱动基因中的六个关键基因组成的预后模型在预测 PC 患者的预后方面具有高度的准确性，并作为独立的危险因素。诱导 TAM2 作为验证这六个基因表达的手段，揭示了 TAM2 细胞中 BCAT1、BST2 和 MERTK 的显著上调。总之，基于 TAM2 驱动基因的免疫表型和预后模型为 PC 的临床管理提供了基础。核心 TAM2 驱动基因，包括 BCAT1、BST2 和 MERTK，参与调节肿瘤进展和 TAM2 极化，是 PC 治疗的潜在靶点。
