Background Peritoneal metastasis is the most common metastasis pattern of gastric cancer. Patients with gastric cancer peritoneal metastasis (GCPM) have a poor prognosis and respond poorly to conventional treatments. Recently, immune checkpoint blockade (ICB) has demonstrated favourable efficacy in the treatment of GCPM. Stratification of best responders and elucidation of resistance mechanisms of ICB therapies are highly important and remain major clinical challenges. Design We performed a phase II trial involving patients with GCPM treated with ICB (sintilimab) combined with chemotherapy. The samples of primary tumours, GCPMs and peripheral blood from patients were collected for single-cell sequencing to comprehensively interpret the tumour microenvironment of GCPM and its impacts on immunotherapy efficacy. Results The GCPM ecosystem coordinates a unique immunosuppressive pattern distinct from that of primary GC, which is dominated by a stroma-myeloid niche composed of SPP1+tumour-associated macrophages (TAMs) and Thrombospondin 2 (THBS2)+matrix cancer-associated fibroblasts (mCAFs). Consequently, this stroma-myeloid crosstalk is the major mediator of ICB resistance in patients with GCPM. Mechanistically, the accumulated THBS2+mCAFs facilitate the recruitment of peritoneum-specific tissue-resident macrophages and their transformation into SPP1+TAMs via the complement C3 and its receptor C3a receptor 1 (C3AR1), thereby forming a protumoral stroma-myeloid niche. Blocking the C3-C3AR1 axis disrupts the stroma-myeloid crosstalk and thereby significantly improves the benefits of ICB in in vivo models. Conclusion Our findings provide a new molecular portrait of cell compositions associated with ICB resistance in patients with GCPM and aid in the prioritisation of therapeutic candidates to potentiate immunotherapy. Data are available in a public, open access repository. Data are available on reasonable request. The sample information is listed in online supplemental table S1. The 10X genomics raw data of this study are deposited in the Genome Sequence Archive for Human database (ID: HRA009064; link: [https://ngdc.cncb.ac.cn/gsa-human/browse/HRA009064][1]). Additionally, the GEXSCOPE single-cell matrix data are deposited in the Mendeley repository (ID: jwkc5t6r55). Previously published scRNA-seq data that were reanalysed and integrated into this study are available in the Gene Expression Omnibus database under accession code GSE183904. All the data that support the findings of this study are available from the corresponding author on reasonable request. [1]: https://ngdc.cncb.ac.cn/gsa-human/browse/HRA009064)

中文翻译：

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肿瘤微环境中的 CAF-巨噬细胞串扰控制胃癌腹膜转移对免疫检查点阻断的反应


背景 腹膜转移是胃癌最常见的转移模式。胃癌腹膜转移 （GCPM） 患者预后不良，对常规治疗反应不佳。最近，免疫检查点阻断 （ICB） 在治疗 GCPM 方面显示出良好的疗效。最佳反应者的分层和 ICB 治疗的耐药机制的阐明非常重要，并且仍然是主要的临床挑战。设计 我们进行了一项 II 期试验，涉及接受 ICB （信迪利单抗） 联合化疗的 GCPM 患者。收集患者原发肿瘤、GCPMs 和外周血样本进行单细胞测序，以全面解读 GCPM 的肿瘤微环境及其对免疫治疗效果的影响。结果 GCPM 生态系统协调一种不同于原发性 GC 的独特免疫抑制模式，该模式由由 SPP1 + 肿瘤相关巨噬细胞 （TAM） 和血小板反应蛋白 2 （THBS2） + 基质癌症相关成纤维细胞 （mCAF） 组成的基质-髓系生态位主导。因此，这种基质-髓系串扰是 GCPM 患者 ICB 耐药的主要介质。从机制上讲，积累的 THBS2+mCAFs 促进腹膜特异性组织驻留巨噬细胞的募集，并通过补体 C3a 受体 1 （C3AR1） 转化为 SPP1+TAM，从而形成前瘤基质-髓系生态位。阻断 C3-C3AR1 轴会破坏基质-髓系串扰，从而显着提高 ICB 在体内模型中的优势。 结论我们的研究结果提供了与 GCPM 患者 ICB 耐药相关的细胞组成的新分子图谱，并有助于优先考虑治疗候选药物以增强免疫治疗。数据在公共、开放访问存储库中可用。数据可应合理要求提供。示例信息列在联机补充表 S1 中。本研究的 10X 基因组学原始数据存放在 Genome Sequence Archive for Human 数据库（ID：HRA009064;链接：[https://ngdc.cncb.ac.cn/gsa-human/browse/HRA009064][1]）中。此外，GEXSCOPE 单细胞基质数据存放在 Mendeley 存储库 （ID： jwkc5t6r55） 中。先前发表的 scRNA-seq 数据经过重新分析并整合到本研究中，可在 Gene Expression Omnibus 数据库中的登录代码 GSE183904下获得。支持本研究结果的所有数据均可在合理要求下从通讯作者处获得。[1]：https://ngdc.cncb.ac。cn/gsa-human/browse/HRA009064）