腹膜转移胃癌分化轨迹和耐药性特征的单细胞表征

IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical and Translational Medicine Pub Date : 2024-10-18 DOI:10.1002/ctm2.70054
Haoxin Peng, Lei Jiang, Jiajia Yuan, Xiangrong Wu, Nan Chen, Dan Liu, Yueting Liang, Yi Xie, Keren Jia, Yanyan Li, Xujiao Feng, Jian Li, Xiaotian Zhang, Lin Shen, Yang Chen
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However, the intricate dynamics within the peritoneal microenvironment (PME) during the treatment process remain largely unknown.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Matched samples from primary tumours (PT), peritoneal metastases (PM), and paired pre-treatment and post-chemo/immunotherapy (anti-PD-1/PD-L1) progression malignant ascites samples, were collected from 48 patients. These samples were subjected to single-cell RNA sequencing (<i>n</i> = 30), multiplex immunofluorescence (<i>n</i> = 30), and spatial transcriptomics (<i>n</i> = 3). 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In the chemoresistant group, intimate interactions between C1Q+ macrophages and fibroblasts through the complement activation pathway were found. In the group demonstrating immunoresistance, heightened TGF-β production activity was detected in MUC1+ cancer cells, and they were skewed to interplay with C1Q+ macrophages through the GDF15-TGF-βR2 axis. 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引用次数: 0

摘要

背景 有腹膜转移(GCPM)的胃癌患者的临床症状会迅速恶化,其特点是耐药和生存率低,尤其是在出现恶性腹水之后。然而,治疗过程中腹膜微环境(PME)内错综复杂的动态变化在很大程度上仍不为人所知。 方法 收集 48 名患者的原发肿瘤(PT)、腹膜转移灶(PM)以及治疗前和化疗/免疫治疗(抗 PD-1/PD-L1)后恶性腹水的配对样本。对这些样本进行了单细胞 RNA 测序(n = 30)、多重免疫荧光(n = 30)和空间转录组学(n = 3)分析。此外,还对一期临床试验(n = 20,NCT03710265)和内部免疫疗法队列(n = 499)进行了事后分析,以验证研究结果。 结果 追踪上皮细胞的进化轨迹发现,终末分化的 MUC1+ 癌细胞具有较高的上皮向间质转化潜能,它们与成纤维细胞和内皮细胞在空间上接近,与不良预后相关。与 PT 和 PM 相比,腹水中的巨噬细胞浸润明显扩大,表现出最高的促血管生成活性。此外,在治疗失败的病例中,较高的C1Q+巨噬细胞浸润与明显较低的GZMA+ T淋巴细胞浸润相关,这可能是由LGALS9-CD45和SPP1-CD44配体-受体相互作用介导的。在化疗耐药组中,发现 C1Q+ 巨噬细胞和成纤维细胞之间通过补体活化途径密切相互作用。在免疫抗体组中,发现 MUC1+ 癌细胞具有更强的 TGF-β 生成活性,而且它们倾向于通过 GDF15-TGF-βR2 轴与 C1Q+ 巨噬细胞相互作用。最终,事后分析表明,对于诊断时出现 GCPM 的患者,联合靶向 TGF-β 和 PDL1 通路可能比单独的抗 PD-1/PD-L1 治疗带来更好的临床疗效。 结论 我们的研究结果阐明了 PME 的细胞分化轨迹和关键耐药特征,有助于探索治疗 GCPM 的有效靶点。 亮点 MUC1+癌细胞具有高度的上皮-间质转化潜能,并在空间上靠近成纤维细胞和内皮细胞,构成了胃癌腹膜转移(GCPM)的驱动力。 在治疗失败的病例中,腹膜微环境中较高的C1Q+巨噬细胞浸润与明显较低的GZMA+ T淋巴细胞浸润相关。 对于确诊为GCPM的患者,联合靶向TGF-β和PDL1通路可能会比单纯的抗PD-1/PD-L1疗法带来更好的临床疗效。
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Single-cell characterization of differentiation trajectories and drug resistance features in gastric cancer with peritoneal metastasis

Background

Gastric cancer patients with peritoneal metastasis (GCPM) experience a rapidly deteriorating clinical trajectory characterized by therapeutic resistance and dismal survival, particularly following the development of malignant ascites. However, the intricate dynamics within the peritoneal microenvironment (PME) during the treatment process remain largely unknown.

Methods

Matched samples from primary tumours (PT), peritoneal metastases (PM), and paired pre-treatment and post-chemo/immunotherapy (anti-PD-1/PD-L1) progression malignant ascites samples, were collected from 48 patients. These samples were subjected to single-cell RNA sequencing (n = 30), multiplex immunofluorescence (n = 30), and spatial transcriptomics (n = 3). Furthermore, post hoc analyses of a phase 1 clinical trial (n = 20, NCT03710265) and an in-house immunotherapy cohort (n = 499) were conducted to validate the findings.

Results

Tracing the evolutionary trajectory of epithelial cells unveiled the terminally differentially MUC1+ cancer cells with a high epithelial-to-mesenchymal transition potential, and they demonstrated spatial proximity with fibroblasts and endothelial cells, correlating with poor prognosis. A significant expansion of macrophage infiltrates, which exhibited the highest proangiogenic activity, was observed in the ascites compared with PT and PM. Besides, higher C1Q+ macrophage infiltrates correlated with significantly lower GZMA+ T-lymphocyte infiltrates in therapeutic failure cases, potentially mediated by the LGALS9-CD45 and SPP1-CD44 ligand–receptor interactions. In the chemoresistant group, intimate interactions between C1Q+ macrophages and fibroblasts through the complement activation pathway were found. In the group demonstrating immunoresistance, heightened TGF-β production activity was detected in MUC1+ cancer cells, and they were skewed to interplay with C1Q+ macrophages through the GDF15-TGF-βR2 axis. Ultimately, post hoc analyses indicated that co-targeting TGF-β and PDL1 pathways may confer superior clinical benefits than sole anti-PD-1/PD-L1 therapy for patients presenting with GCPM at the time of diagnosis.

Conclusions

Our findings elucidated the cellular differentiation trajectories and crucial drug resistance features within PME, facilitating the exploration of effective targets for GCPM treatment.

Highlights

  • MUC1+ cancer cells with a high epithelial-to-mesenchymal transition potential and exhibiting spatial proximity to fibroblasts and endothelial cells constitute the driving force of gastric cancer peritoneal metastasis (GCPM).
  • Higher C1Q+ macrophage infiltrates correlated with significantly lower GZMA+ T-lymphocyte infiltrates within the peritoneal microenvironment in therapeutic failure cases.
  • Co-targeting TGF-β and PDL1 pathways may confer superior clinical benefits than sole anti-PD-1/PD-L1 therapy for patients presenting with GCPM at diagnosis.
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来源期刊
CiteScore
15.90
自引率
1.90%
发文量
450
审稿时长
4 weeks
期刊介绍: Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
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