Yu Hongliang, Gu Dayong, Yue Chao, Xu Jianhua, Yan Feng, He Xia
Department of Radiation Oncology, Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China.
Department of General Surgery, Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China.
Front Oncol. 2021 Apr 1;11:636479. doi: 10.3389/fonc.2021.636479. eCollection 2021.
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest solid malignancies and has a poor survival rate worldwide. In this study, we aimed to establish a tumor-infiltrating immune cell-based prognosis signature (IPS) to predict patients' survival times and aid in the development of targeted therapies or immunotherapies. The abundances of 22 types of immune cells were determined by the CIBERSORT algorithm from ESCC patient gene expression data in the Gene Expression Omnibus (GEO) training set (n = 179) and The Cancer Genome Atlas (TCGA) validation set (n = 95). Then, the IPS was established by using the least absolute shrinkage and selection operator (LASSO) regression method. Kaplan-Meier analysis showed that patients with high IPS scores had significantly worse overall survival times than patients with low IPS scores in both the training set and the validation set (log-rank p = 0.001, and p = 0.050, respectively). Univariate and multivariate Cox regression analyses proved that the IPS was a robust prognostic factor for ESCC, independent of age, sex, tumor node metastasis (TNM) stage, pathology grade, and tumor location. In the mechanistic study, the epithelial-mesenchymal transition (EMT) process was identified by both gene set enrichment analysis (GSEA) and weighted correlation network analysis (WGCNA) as the underlying mechanism by which the IPS affects the prognosis of ESCC. After systematic correlation analyses, we found that M2 macrophages were the only cell type in the IPS significantly correlated with the EMT process. This relationship between M2 macrophage infiltration and the EMT phenotype was also confirmed by our preliminary immunochemistry (IHC) and multiplexed immunofluorescence study. In conclusion, we constructed an IPS that predicts the postoperative prognosis of ESCC patients and uncovered the critical role of M2 macrophages in the interplay between immune status and the EMT phenotype in ESCC.
食管鳞状细胞癌（ESCC）是最致命的实体恶性肿瘤之一，在全球范围内生存率较低。在本研究中，我们旨在建立一种基于肿瘤浸润免疫细胞的预后特征（IPS），以预测患者的生存时间，并有助于开发靶向治疗或免疫治疗。通过CIBERSORT算法从基因表达综合数据库（GEO）训练集（n = 179）和癌症基因组图谱（TCGA）验证集（n = 95）中的ESCC患者基因表达数据确定22种免疫细胞的丰度。然后，使用最小绝对收缩和选择算子（LASSO）回归方法建立IPS。Kaplan-Meier分析表明，在训练集和验证集中，IPS评分高的患者总生存时间明显低于IPS评分低的患者（对数秩检验p分别为0.001和0.050）。单因素和多因素Cox回归分析证明，IPS是ESCC的一个稳健预后因素，独立于年龄、性别、肿瘤淋巴结转移（TNM）分期、病理分级和肿瘤位置。在机制研究中，基因集富集分析（GSEA）和加权相关网络分析（WGCNA）均确定上皮-间质转化（EMT）过程是IPS影响ESCC预后的潜在机制。经过系统的相关性分析，我们发现M2巨噬细胞是IPS中唯一与EMT过程显著相关的细胞类型。我们的初步免疫组织化学（IHC）和多重免疫荧光研究也证实了M2巨噬细胞浸润与EMT表型之间的这种关系。总之，我们构建了一种预测ESCC患者术后预后的IPS，并揭示了M2巨噬细胞在ESCC免疫状态与EMT表型相互作用中的关键作用。
