Liu Xiaopei, Liu Dan, Tan Cong'e, Wang Jiehong
School of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China.
Department of Anorectal, Xi'an Hospital of Traditional Chinese Medicine, Xianyang, China.
Medicine (Baltimore). 2024 Dec 27;103(52):e40979. doi: 10.1097/MD.0000000000040979.
Colon cancer (COAD) poses great challenges to clinical treatment due to its heterogeneity and complex immune microenvironment. M2-like macrophages significantly influence COAD's onset, progression, and treatment. Yet, existing M2-like macrophage markers are limited in prognostic efficacy, prompting the exploration of new M2 signatures. Extensive data analysis aimed to unveil prognosis-associated M2-derived signatures. Bulk transcriptome, single-cell RNA sequencing, and clinical data from The Cancer Genome Atlas and Gene Expression Omnibus databases for patients with COAD were amassed. Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts identified immune cell infiltration, and the Kaplan-Meier test identified crucial immune populations associated with prognosis. Genetic signatures linked to M2 tumor-associated macrophage were crafted utilizing weighted gene coexpression network analysis, least absolute shrinkage and selection operator, and Cox regression. The M2 tumor-associated macrophage gene signature was validated in GSE17536. The expression profile of the M2 gene signature was investigated in single-cell RNA sequencing dataset GSE166555. Systemic immune profile identified that M2-like macrophage has the most significant prognostic significance in The Cancer Genome Atlas-COAD. The core genes related to M2 macrophage infiltration were extracted by weighted gene coexpression network analysis. Least absolute shrinkage and selection operator-stepwise COX regression-derived M2-derived signatures (snail family zinc finger 1, gastrin-releasing peptide, gamma-aminobutyric acid type A receptor delta subunit, cluster of differentiation 1B, poly(A)-binding protein cytoplasmic 2, manic fringe, and death-associated protein kinase 1) as a risk model, which was confirmed as independent prognosis factors, validated by external dataset. This M2-based prognostic model reflected M2 macrophage infiltration. Mendelian randomization established cytotoxic T lymphocyte associate protein-4 and cluster of differentiation 274 immune checkpoints' causality with COAD. In conclusion, our study developed novel markers for discriminating M2-like macrophages and predicting the prognosis of patients with COAD, offering fresh perspectives for clinical interventions.
由于其异质性和复杂的免疫微环境，结肠癌（COAD）给临床治疗带来了巨大挑战。M2样巨噬细胞对COAD的发生、发展和治疗有显著影响。然而，现有的M2样巨噬细胞标志物在预后效能方面存在局限性，这促使人们探索新的M2特征。广泛的数据分析旨在揭示与预后相关的M2衍生特征。收集了来自癌症基因组图谱（The Cancer Genome Atlas）和基因表达综合数据库（Gene Expression Omnibus）的COAD患者的批量转录组、单细胞RNA测序和临床数据。通过估计RNA转录本相对子集进行细胞类型鉴定来识别免疫细胞浸润，Kaplan-Meier检验确定与预后相关的关键免疫群体。利用加权基因共表达网络分析、最小绝对收缩和选择算子以及Cox回归构建与M2肿瘤相关巨噬细胞相关的基因特征。在GSE17536中验证了M2肿瘤相关巨噬细胞基因特征。在单细胞RNA测序数据集GSE166555中研究了M2基因特征的表达谱。系统免疫分析表明，M2样巨噬细胞在癌症基因组图谱-COAD中具有最显著的预后意义。通过加权基因共表达网络分析提取与M2巨噬细胞浸润相关的核心基因。最小绝对收缩和选择算子-逐步COX回归衍生的M2衍生特征（蜗牛家族锌指蛋白1、胃泌素释放肽、γ-氨基丁酸A型受体δ亚基、分化簇1B、聚腺苷酸结合蛋白细胞质2、疯狂边缘蛋白和死亡相关蛋白激酶1）作为风险模型，被确认为独立的预后因素，并通过外部数据集进行了验证。这种基于M2的预后模型反映了M2巨噬细胞浸润。孟德尔随机化确定了细胞毒性T淋巴细胞相关蛋白4和分化簇274免疫检查点与COAD的因果关系。总之，我们的研究开发了用于区分M2样巨噬细胞和预测COAD患者预后的新型标志物，为临床干预提供了新的视角。
