Early Immune Changes Support Signet Ring Cell Dormancy in CDH1-Driven Hereditary Diffuse Gastric Carcinogenesis.
Early Immune Changes Support Signet Ring Cell Dormancy in CDH1-Driven Hereditary Diffuse Gastric Carcinogenesis.
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早期免疫变化支持 CDH1 驱动的遗传性弥漫性胃癌中印戒细胞休眠。
DOI：
10.1158/1541-7786.mcr-23-0122
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Davis,Jere
中科院分区：
文献类型：
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作者：
Green,BenjaminL;Gamble,LaurenA;Diggs,LaurenceP;Nousome,Darryl;Patterson,JesseC;Joughin,BrianA;Gasmi,Billel;Lux,StephanieC;Samaranayake,SarahG;Miettinen,Markku;Quezado,Martha;Hernandez,JonathanM;Yaffe,MichaelB;Davis,Jere
IA期胃腺癌，以粘膜内印环细胞（SRC）灶为特征，见于几乎所有无症状的种系致病性cdh1变异和遗传性弥漫性胃癌综合征（HDGC）患者。在HDGC中启动恶性转化和促进SRC休眠的分子步骤尚不清楚。在这里，研究人员对HDGC患者全胃切除标本中发现的可降低风险的微解剖（LCM）区域进行了src和邻近非src上皮（NEP）的全外显子组大体积RNA测序（RNA-seq）。共发现20例确诊的HDGC患者（6男14女）。差异表达基因（DEG）分析显示，某些个体EMT和增殖基因上调。然而，在src中未发现任何致癌途径上调。相反，SRC区域在t细胞信号通路中有显著的富集。CIBERSORTx预测SRC区域特异性调节性T细胞（Treg）存在显著增加。免疫组化证实，SRC灶中FOXP3+细胞增多，CD4+T细胞和HLA-DR染色升高。综上所述，通过颗粒分离技术，肿瘤免疫微环境与IA期胃src在显微镜下是不可分离的。SRC区域内CD4+T细胞的升高与临床观察到的SRC休眠有关，而Treg上调代表了一种潜在的免疫逃逸机制。HDGC中肿瘤免疫微环境的特征强调了免疫系统塑造早期肿瘤转录谱的潜力，这表明免疫定向治疗是弥漫性胃癌的潜在癌症拦截策略。
Stage IA gastric adenocarcinoma, characterized by foci of intramucosal signet ring cells (SRC), is found in nearly all asymptomatic patients with germline pathogenicCDH1variants and hereditary diffuse gastric cancer syndrome (HDGC). The molecular steps involved in initiating malignant transformation and promoting SRC dormancy in HDGC are unknown. Here, whole-exome bulk RNA sequencing (RNA-seq) of SRCs and adjacent non-SRC epithelium (NEP) was performed on laser-capture microdissected (LCM) regions of interest found in risk-reducing total gastrectomy specimens from patients with HDGC (Clinicaltrials.gov ID: NCT03030404). In total, 20 patients (6 male, 14 female) with confirmed HDGC were identified. Analysis of differentially expressed genes (DEG) demonstrated upregulation of certain individual EMT and proliferation genes. However, no oncogenic pathways were found to be upregulated in SRCs. Rather, SRC regions had significant enrichment in pathways involved in T-cell signaling. CIBERSORTx predicted significant increases in the presence of regulatory T cells (Treg) specific to SRC regions. IHC confirmed an increase in FOXP3+cells in SRC foci, as well as elevations in CD4+T cells and HLA-DR staining. In summary, the tumor immune microenvironment is microscopically inseparable from stage IA gastric SRCs using a granular isolation technique. An elevation in CD4+T cells within SRC regions correlates with clinically observed SRC dormancy, while Treg upregulation represents a potential immune escape mechanism.ImplicationsCharacterization of the tumor–immune microenvironment in HDGC underscores the potential for the immune system to shape the transcriptional profile of the earliest tumors, which suggests immune-directed therapy as a potential cancer interception strategy in diffuse-type gastric cancer.