| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Clinical and Translational Medicine, Vol 14, Iss 10, Pp n/a-n/a (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2001-1326 |
| DOI: |
10.1002/ctm2.70054 |
| Popis: |
Abstract 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. |
| Databáze: |
Directory of Open Access Journals |
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