Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, 350001, Fujian, China.
Sci Rep. 2024 Oct 31;14(1):26221. doi: 10.1038/s41598-024-76298-w.
Immunotherapy has become a primary and secondary treatment for gastric cancer (GC) patients with mismatch repair deficiency (dMMR), and is used in both perioperative and advanced stages. The tumor immune microenvironment (TiME) is crucial for immunotherapy efficacy, yet the impact of MMR status on TiME remains understudied. We employed single-cell RNA sequencing (scRNA-seq) to analyze 33 fresh tissue samples from 25 patients, which included 10 normal tissues, 6 dMMR tumor tissues, and 17 pMMR tumor tissues, aiming to characterize the cellular and molecular components of the TiME. The proficient mismatch repair (pMMR) group displayed a significantly higher prevalence of a specific GC cell type, termed GC2, characterized by increased hypoxia, epithelial-mesenchymal transition (EMT), and angiogenic activities compared to the dMMR group. GC2 cells overexpressed BEX3 and GPC3, and they significantly correlated with poorer survival. The pMMR group also showed increased infiltration of SPP1 + macrophages and FAP + fibroblasts, exhibiting strong hypoxic and pro-angiogenic features. Furthermore, a higher proportion of E2 endothelial cells, involved in extracellular matrix (ECM) remodeling and showing heightened VEGF pathway, HIF pathway, and angiogenesis activity, were identified in pMMR patients. Intercellular communication analyses revealed that GC2 cells, SPP1 + macrophages, FAP + fibroblasts, and E2 endothelial cells interact through VEGF, SPP1, and MIF signals, forming a TiME characterized by hypoxia, pro-angiogenesis, and ECM remodeling. This study uncovered TiME heterogeneity among GC patients with different MMR states, highlighting that the pMMR TiME is distinguished by hypoxia, pro-angiogenesis, and ECM remodeling, driven by the presence of GC2 cells, SPP1 + macrophages, FAP + fibroblasts, and E2 endothelial cells. These findings are pivotal for developing targeted immunotherapies for GC patients with pMMR.
免疫疗法已成为错配修复缺陷（dMMR）胃癌（GC）患者的一线和二线治疗方法，并在围手术期和晚期均有应用。肿瘤免疫微环境（TiME）对于免疫疗法的疗效至关重要，但 MMR 状态对 TiME 的影响仍研究不足。我们采用单细胞 RNA 测序（scRNA-seq）分析了 25 名患者的 33 份新鲜组织样本，其中包括 10 份正常组织、6 份 dMMR 肿瘤组织和 17 份 pMMR 肿瘤组织，旨在描述 TiME 的细胞和分子组成。功能型错配修复（pMMR）组中一种特定的 GC 细胞类型（GC2）的发生率明显更高，其特点是缺氧、上皮间质转化（EMT）和血管生成活性增加，与 dMMR 组相比。GC2 细胞过度表达 BEX3 和 GPC3，与生存率降低显著相关。pMMR 组还显示 SPP1+巨噬细胞和 FAP+成纤维细胞浸润增加，表现出强烈的缺氧和促血管生成特征。此外，pMMR 患者中发现了更高比例的 E2 内皮细胞，其参与细胞外基质（ECM）重塑，并表现出更高的 VEGF 通路、HIF 通路和血管生成活性。细胞间通讯分析表明，GC2 细胞、SPP1+巨噬细胞、FAP+成纤维细胞和 E2 内皮细胞通过 VEGF、SPP1 和 MIF 信号相互作用，形成一个以缺氧、促血管生成和 ECM 重塑为特征的 TiME。本研究揭示了不同 MMR 状态的 GC 患者之间 TiME 的异质性，强调了 pMMR TiME 的特点是缺氧、促血管生成和 ECM 重塑，由 GC2 细胞、SPP1+巨噬细胞、FAP+成纤维细胞和 E2 内皮细胞的存在驱动。这些发现对于开发针对 pMMR 的 GC 患者的靶向免疫疗法至关重要。
