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Updated: Jul 18, 2025
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Single cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver
Shu Zhang1,2,3,4, Wen Fang3, Siqi Zhou4
1Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies. However, our understanding of PDAC microenvironment especially the metastatic microenvironment is very limited partly due to the inaccessibility to metastatic tumor tissues. Here, we present the single-cell transcriptomic landscape of synchronously resected PDAC primary tumors and matched liver metastases. We perform comparative analysis on both cellular composition and functional phenotype between primary and metastatic tumors. Tumor cells exhibit distinct transcriptomic profile in liver metastasis with clearly defined evolutionary routes from cancer cells in primary tumor. We also identify specific subtypes of stromal and immune cells critical to the formation of the pro-tumor microenvironment in metastatic lesions, including RGS5+ cancer-associated fibroblasts, CCL18+ lipid-associated macrophages, S100A8+ neutrophils and FOXP3+ regulatory T cells. Cellular interactome analysis further reveals that the lack of tumor-immune cell interaction in metastatic tissues contributes to the formation of the immunosuppressive microenvironment. Our study provides a comprehensive characterization of the transcriptional landscape of PDAC liver metastasis.
Insights
This study reveals key differences in pancreatic cancer liver metastases compared to primary tumors. It identifies specific cell types and interactions that create a pro-tumor, immunosuppressive environment, offering new insights into pancreatic ductal adenocarcinoma progression.
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with limited treatment options.
- Understanding the metastatic microenvironment is crucial but challenging due to tissue inaccessibility.
Purpose of the Study:
- To characterize the single-cell transcriptomic landscape of PDAC liver metastases.
- To compare cellular composition and function between primary and metastatic PDAC.
- To identify key cellular players and interactions in the metastatic microenvironment.
Main Methods:
- Single-cell RNA sequencing of matched primary PDAC tumors and liver metastases.
- Comparative transcriptomic analysis of tumor, stromal, and immune cells.
- Cellular interactome analysis.
Main Results:
- PDAC tumor cells show distinct transcriptomic profiles in liver metastases with defined evolutionary paths.
- Specific pro-tumorigenic stromal and immune cell subtypes were identified in metastases (e.g., RGS5+ fibroblasts, CCL18+ macrophages, S100A8+ neutrophils, FOXP3+ Tregs).
- Reduced tumor-immune cell interactions were observed in metastatic sites, fostering immunosuppression.
Conclusions:
- The study provides a detailed map of the PDAC liver metastatic microenvironment.
- Identified cellular players and interactions offer potential therapeutic targets.
- Findings advance understanding of PDAC metastasis and immune evasion.
