CAF-macrophage crosstalk in tumour microenvironments governs the response to immune checkpoint blockade in gastric cancer peritoneal metastases

IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Gut Pub Date : 2024-11-12 DOI:10.1136/gutjnl-2024-333617
Yuanfang Li, Yongqiang Zheng, Jiaqian Huang, Run-Cong Nie, Qi-Nian Wu, Zhijun Zuo, Shuqiang Yuan, Kai Yu, Cheng-Cai Liang, Yi-Qian Pan, Bai-Wei Zhao, Yuhong Xu, Qihua Zhang, Yashang Zheng, Junquan Chen, Zhao-Lei Zeng, Wei Wei, Ze-Xian Liu, Rui-Hua Xu, Hui-Yan Luo
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Abstract

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)
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肿瘤微环境中的 CAF-巨噬细胞串扰影响胃癌腹膜转移灶对免疫检查点阻断剂的反应
背景 腹膜转移是胃癌最常见的转移方式。胃癌腹膜转移(GCPM)患者的预后较差,对常规治疗反应不佳。最近,免疫检查点阻断疗法(ICB)在治疗胃癌腹膜转移方面取得了良好疗效。对最佳应答者进行分层并阐明ICB疗法的耐药机制非常重要,这仍是主要的临床挑战。设计 我们对接受 ICB(辛替利单抗)联合化疗的 GCPM 患者进行了一项 II 期试验。我们采集了患者的原发肿瘤、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疗法疗效的影响。结果 GCPM 生态系统具有独特的免疫抑制模式,不同于原发性 GC 的免疫抑制模式,其主要特征是由 SPP1+肿瘤相关巨噬细胞(TAM)和血栓软骨素 2(THBS2)+基质癌相关成纤维细胞(mCAF)组成的基质-髓细胞龛。因此,这种基质-髓系串扰是 GCPM 患者对 ICB 产生耐药性的主要介质。从机制上讲,累积的 THBS2+mCAFs 可通过补体 C3 及其受体 C3a 受体 1 (C3AR1),促进腹膜特异性组织驻留巨噬细胞的募集并转化为 SPP1+TAMs,从而形成原瘤基质-髓系龛。阻断 C3-C3AR1 轴可破坏基质-髓系串联,从而显著改善 ICB 在体内模型中的疗效。结论 我们的研究结果提供了与 GCPM 患者 ICB 耐药性相关的细胞组成的新分子画像,有助于确定候选疗法的优先次序,以增强免疫疗法的疗效。数据可在公开、开放的资源库中获取。如有合理要求,可提供数据。样本信息见在线补充表 S1。本研究的 10X 基因组原始数据已存入人类基因组序列档案数据库(ID:HRA009064;链接:[][1]):[https://ngdc.cncb.ac.cn/gsa-human/browse/HRA009064][1])。此外,GEXSCOPE 单细胞矩阵数据已存入 Mendeley 数据库(ID:jwkc5t6r55)。以前发表的 scRNA-seq 数据经过重新分析并整合到本研究中,这些数据可在基因表达总库(Gene Expression Omnibus)数据库中查阅,登录代码为 GSE183904。支持本研究结果的所有数据可向通讯作者索取。[1]: https://ngdc.cncb.ac.cn/gsa-human/browse/HRA009064)
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来源期刊
Gut
Gut 医学-胃肠肝病学
CiteScore
45.70
自引率
2.40%
发文量
284
审稿时长
1.5 months
期刊介绍: Gut is a renowned international journal specializing in gastroenterology and hepatology, known for its high-quality clinical research covering the alimentary tract, liver, biliary tree, and pancreas. It offers authoritative and current coverage across all aspects of gastroenterology and hepatology, featuring articles on emerging disease mechanisms and innovative diagnostic and therapeutic approaches authored by leading experts. As the flagship journal of BMJ's gastroenterology portfolio, Gut is accompanied by two companion journals: Frontline Gastroenterology, focusing on education and practice-oriented papers, and BMJ Open Gastroenterology for open access original research.
期刊最新文献
Correction: The road to a world-unified approach to the management of patients with gastric intestinal metaplasia: a review of current guidelines CAF-macrophage crosstalk in tumour microenvironments governs the response to immune checkpoint blockade in gastric cancer peritoneal metastases Recent advances in clinical practice: mastering the challenge—managing IBS symptoms in IBD Large proximal gastric GIST tumours: downsizing by imatinib and subsequent endoresection Proton pump inhibitors and the risk of inflammatory bowel disease: a Mendelian randomisation study.
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