SPP1+ macrophages and FAP+ fibroblasts promote the progression of pMMR gastric cancer.
FAP+ fibroblasts
Gastric cancer
Immunotherapy
Mismatch repair
SPP1+ macrophage
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
31 Oct 2024
31 Oct 2024
Historique:
received:
12
02
2024
accepted:
11
10
2024
medline:
1
11
2024
pubmed:
1
11
2024
entrez:
1
11
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39482333
doi: 10.1038/s41598-024-76298-w
pii: 10.1038/s41598-024-76298-w
doi:
Substances chimiques
fibroblast activation protein alpha
EC 3.4.21.-
Gelatinases
EC 3.4.24.-
Membrane Proteins
0
Endopeptidases
EC 3.4.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
26221Subventions
Organisme : Joint Funds for the Innovation of Science and Technology, Fujian Province
ID : No.2023Y9342
Organisme : Special Grant for Education and Scientific Research of Fujian Provincial Department of Finance
ID : Fujian Finance Document (2023) 834
Informations de copyright
© 2024. The Author(s).
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