Department of Clinical Medicine, Medical College of Soochow University, Suzhou 215006, People's Republic of China; Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, People's Republic of China.
Department of Endocrinology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, People's Republic of China.
Gene. 2022 Apr 15;818:146177. doi: 10.1016/j.gene.2021.146177. Epub 2022 Jan 20.
In primary stomach adenocarcinoma (STAD), the tumor immune microenvironment (TIME) is important for cancer occurrence and progression; however, its clinical significance remains unclear. This study investigated the association between patient survival, TIME, and therapeutic response to STAD.
Gene expression profiles of STAD cases were collected from the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus. Molecular subtypes were explored with consistent clustering methods according to 119 immune signatures and the infiltrating scores of 22 immune cells using the Multi-Omics Immuno-Oncology Biological Research algorithm. We determined IFNγ scores and immune cytolytic activity (CYT) scores on the basis of corresponding gene signatures via single-sample Gene Set Enrichment Analysis. Comparisons of survival, TIME, 10 immunity-related oncogenic pathways, immune checkpoint expression, and therapeutic response were conducted among the three subtypes. We further applied linear discriminant analysis to construct a characteristic index to classify the subtypes, and the Pearson correlation coefficient for the relationship between the index and immune checkpoint genes. Weighted Correlation Network Analysis (WGCNA) was used to mine the associated modules and specific genes.
We collected gene expression profiles from 352 STAD cases in the TCGA database, 300 in GSE62254, and 344 in GSE84437. Three STAD subtypes (IS1-IS3) were established according to the TIME signatures. The IS3 subtype had the highest immune score and the best prognosis, as well as markedly increased immune T-cell CYT, Th1/IFNγ scores, and immune checkpoint gene expression, compared to the other two subtypes. It was highly similar to the PD-1 response group in the previous study samples of GSE91061. The established TIME classification index performed well in classifying subtypes and was directly proportional to immune checkpoint-related gene expression levels. WGCNA explored 6 modules and 14 genes, namely DYSF, MAN1C1, HTRA3, EMCN, RFLNB, KANK3, MAGEH1, CD93, PCAT19, FUT11, BMP1, FOSB, DCHS1, and TCF3, which were associated with the established TIME classification index and STAD patient prognosis.
TIME phenotypes of STAD patients could be divided into three different molecular subtypes, which displayed different prognoses, immune features, and therapeutic responses. Our results shed new light on predicting patient outcomes and the discovery of new anti-STAD therapeutic strategies according to the TIME.
在原发性胃腺癌（STAD）中，肿瘤免疫微环境（TIME）对癌症的发生和发展很重要；然而，其临床意义尚不清楚。本研究探讨了 STAD 患者生存、TIME 与治疗反应之间的关系。
从癌症基因组图谱（TCGA）数据库和基因表达综合数据库中收集了 STAD 病例的基因表达谱。使用 Multi-Omics Immuno-Oncology Biological Research 算法，根据 119 个免疫特征和 22 种免疫细胞的浸润评分，采用一致聚类方法对分子亚型进行探索。我们通过单样本基因集富集分析，基于相应的基因特征确定 IFNγ 评分和免疫细胞溶解性（CYT）评分。在三个亚型之间进行了生存、TIME、10 个与免疫相关的致癌途径、免疫检查点表达和治疗反应的比较。我们进一步应用线性判别分析构建了一个特征指数来对亚型进行分类，并计算了指数与免疫检查点基因之间的皮尔逊相关系数。采用加权相关网络分析（WGCNA）挖掘相关模块和特定基因。
我们从 TCGA 数据库中收集了 352 例 STAD 病例的基因表达谱，从 GSE62254 中收集了 300 例，从 GSE84437 中收集了 344 例。根据 TIME 特征，建立了三种 STAD 亚型（IS1-IS3）。与其他两种亚型相比，IS3 亚型具有最高的免疫评分和最好的预后，以及显著增加的免疫 T 细胞 CYT、Th1/IFNγ 评分和免疫检查点基因表达。它与之前研究样本 GSE91061 中的 PD-1 反应组高度相似。建立的 TIME 分类指数在对亚型进行分类方面表现良好，与免疫检查点相关基因的表达水平呈直接正相关。WGCNA 共探讨了 6 个模块和 14 个基因，即 DYSF、MAN1C1、HTRA3、EMCN、RFLNB、KANK3、MAGEH1、CD93、PCAT19、FUT11、BMP1、FOSB、DCHS1 和 TCF3，它们与建立的 TIME 分类指数和 STAD 患者预后相关。
STAD 患者的 TIME 表型可分为三种不同的分子亚型，它们表现出不同的预后、免疫特征和治疗反应。我们的研究结果为根据 TIME 预测患者预后和发现新的抗 STAD 治疗策略提供了新的视角。
