Wang Qingyuan, Chen Jia, Wang Yaohui, Li Xiang, Ping Xiaochun, Shen Jiajia, Yang Sheng, Shen Lizong
Departemtn of General Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
Department of General Surgery, Northern Jiangsu People's Hospital, Yangzhou, 225001, Jiangsu, China.
Cancer Immunol Immunother. 2025 Feb 1;74(3):82. doi: 10.1007/s00262-024-03938-5.
Gastric adenocarcinoma (GAC), particularly the Lauren intestinal-type GAC (IGAC), leads to significant mortality in China due to the limited effectiveness of current treatments. This study aims to investigate the mechanisms of immune suppression in IGAC to identify potential targets for enhancing immunotherapy outcomes.
Performing an extensive collection and re-analysis of single-cell RNA sequencing (scRNA-seq) of tumor tissues and the corresponding noncancerous mucosae from 15 Chinese patients diagnosed with IGAC, we identified cell subpopulations involved in immune suppression within the tumor microenvironment (TME). We further validated our findings using spatially resolved transcriptomics (SRT), immunofluorescence (IF), and flow cytometry (FCM) on tissues from IGAC patients.
We demonstrated that the TME of IGAC harbors CD8 exhausted T cells (Texs) and various subtypes that mediate immunity. We identified specific subpopulations of Texs (HAVCR2VCAM1) and regulatory T cells (Tregs) (LAYNTNFRSF4) contributing to immune suppression. Furthermore, TNFRSF12A cancer-associated fibroblasts (CAFs), CTSB macrophages, and SOD2 monocytes were found to be involved in maintaining the immunosuppressive milieu. SRT and IF assays confirmed the presence and colocalization of these cell types within the tumor tissues, highlighting their functional interactions. FCM assays indicated that the prevalence of HAVCR2VCAM1 Texs and LAYNTNFRSF4 Tregs in tumor tissues was positively associated with IGAC progression.
Detailed profiles of immunosuppressive cell subpopulations in IGAC provide valuable insights into the complexity and heterogeneity of immunosuppression. These findings underscore the necessity for targeted strategies that disrupt specific immunosuppressive pathways, potentially enhancing the efficacy of immunotherapeutic interventions in IGAC.
胃腺癌（GAC），尤其是劳伦肠型胃腺癌（IGAC），由于目前治疗效果有限，在中国导致了很高的死亡率。本研究旨在探究IGAC中免疫抑制的机制，以确定增强免疫治疗效果的潜在靶点。
对15例诊断为IGAC的中国患者的肿瘤组织及相应的癌旁黏膜进行单细胞RNA测序（scRNA-seq）的广泛收集和重新分析，我们确定了肿瘤微环境（TME）中参与免疫抑制的细胞亚群。我们进一步使用空间分辨转录组学（SRT）、免疫荧光（IF）和流式细胞术（FCM）对IGAC患者的组织进行验证。
我们证明IGAC的TME中存在CD8耗竭性T细胞（Texs）和介导免疫的各种亚型。我们确定了有助于免疫抑制的Texs（HAVCR2VCAM1）和调节性T细胞（Tregs）（LAYNTNFRSF4）的特定亚群。此外，发现肿瘤坏死因子受体超家族成员12A 癌症相关成纤维细胞（CAFs）、组织蛋白酶B巨噬细胞和超氧化物歧化酶2单核细胞参与维持免疫抑制环境。SRT和IF分析证实了这些细胞类型在肿瘤组织中的存在和共定位，突出了它们的功能相互作用。FCM分析表明，肿瘤组织中HAVCR2VCAM1 Texs和LAYNTNFRSF4 Tregs的比例与IGAC进展呈正相关。
IGAC中免疫抑制细胞亚群的详细图谱为免疫抑制的复杂性和异质性提供了有价值的见解。这些发现强调了破坏特定免疫抑制途径的靶向策略的必要性，这可能会提高IGAC免疫治疗干预的疗效。
