免疫亚型的综合分析揭示了胃腺癌中细胞毒性和 FAP 成纤维细胞的预后价值。
Comprehensive analysis of immune subtypes reveals the prognostic value of cytotoxicity and FAP fibroblasts in stomach adenocarcinoma.
机构信息
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
出版信息
Cancer Immunol Immunother. 2023 Jun;72(6):1763-1778. doi: 10.1007/s00262-023-03368-9. Epub 2023 Jan 17.
BACKGROUND
The heterogeneity limits the effective application of immune checkpoint inhibitors for patients with stomach adenocarcinoma (STAD). Precise immunotyping can help select people who may benefit from immunotherapy and guide postoperative management by describing the characteristics of tumor microenvironment.
METHODS
Gene expression profiles and clinical information of patients were collected from ACRG and TCGA-STAD datasets. The immune subtypes (ISs) were identified by consensus clustering analysis. The tumor immune microenvironments (TIME) of each IS were characterized using a series of immunogenomics methods and further confirmed by multiplex immunohistochemistry (mIHC) staining in clinical samples. Two online datasets and one in-house dataset were utilized to construct and validate a prognostic immune-related gene (IRG) signature.
RESULTS
STAD patients were stratified into five reproducible ISs. IS1 (immune deserve subtype) had low immune infiltration and the highest degree of HER2 gene mutation. With abundant CD8 T cells infiltration and activated cytotoxicity reaction, patients in the IS2 (immune-activated subtype) had the best overall survival (OS). IS3 and IS4 subtypes were both in the reactive stroma state and indicated the worst prognosis. However, IS3 (immune-inhibited subtype) was characterized by enrichment of FAP fibroblasts and upregulated TGF-β signaling pathway, while IS4 (activated stroma subtype) was characterized by enrichment of ACTA2 fibroblasts. In addition, mIHC staining confirmed that TGF-β upregulated FAP fibroblasts were independent risk factor of OS. IS5 (chronic inflammation subtype) displayed moderate immune cells infiltration and had a relatively good survival. Lastly, we developed a nine-IRG signature model with a robust performance on overall survival prognostication.
CONCLUSIONS
The immunotyping is indicative for characterize the TIME heterogeneity and the prediction of tumor prognosis for STADs, which may provide valuable stratification for the design of future immunotherapy.
背景
胃腺癌（STAD）患者的异质性限制了免疫检查点抑制剂的有效应用。精准免疫分型可以通过描述肿瘤微环境的特征，帮助选择可能受益于免疫治疗的人群，并指导术后管理。
方法
从 ACRG 和 TCGA-STAD 数据集收集患者的基因表达谱和临床信息。通过共识聚类分析确定免疫亚型（IS）。采用一系列免疫基因组学方法对每个 IS 的肿瘤免疫微环境（TIME）进行特征描述，并在临床样本中通过多重免疫组化（mIHC）染色进一步验证。利用两个在线数据集和一个内部数据集构建和验证预后免疫相关基因（IRG）特征。
结果
将 STAD 患者分为五个可重复的 IS。IS1（免疫应得亚型）具有低免疫浸润和最高程度的 HER2 基因突变。IS2（免疫激活亚型）的 CD8 T 细胞浸润丰富，细胞毒性反应活跃，患者总体生存率（OS）最佳。IS3 和 IS4 亚型均处于反应性基质状态，预后最差。然而，IS3（免疫抑制亚型）的特征是富含 FAP 成纤维细胞，并上调 TGF-β信号通路，而 IS4（激活基质亚型）的特征是富含 ACTA2 成纤维细胞。此外，mIHC 染色证实 TGF-β上调的 FAP 成纤维细胞是 OS 的独立危险因素。IS5（慢性炎症亚型）显示出中等程度的免疫细胞浸润，生存情况相对较好。最后，我们开发了一个由 9 个 IRG 组成的特征模型，对总体生存率的预后具有强大的性能。
结论
免疫分型可用于描述 STAD 肿瘤的 TIME 异质性和预测肿瘤预后，这可能为未来免疫治疗的设计提供有价值的分层。
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