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Updated: Apr 23, 2026
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates natural killer cell dysfunction
Yun-Peng Peng, Jing-Jing Zhang, Wen-biao Liang
1Department of General Surgery, The first Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, People's Republic of China. miaoyi@njmu.edu.cn.
Background:
Natural killer (NK) cells play a key role in non-specific immune response in different cancers, including pancreatic cancer. However the anti-tumor effect of NK cells decreases during pancreatic cancer progression. The regulatory pathways by which NK cells facilitate tumor immune escape are unclear, therefore our purpose was to investigate the roles of the contributory factors.
Methods:
NK cells isolated from fresh healthy peripheral blood were co-cultured with normal human pancreatic ductal cells hTERT-HPNE and human pancreatic cancer cell lines SW1990 and BxPc-3 in vitro. Then NK cell function was determined by Flow cytometric analysis of surface receptors and cytotoxic granules in NK cells, NK cell apoptosis and cytotoxicity, and Enzyme-linked immunosorbent assay of cytokines. Expression level of MMP-9, IDO and COX-2 in hTERT-HPNE and SW1990 cells were detected by quantitative RT-PCR. Statistical differences between data groups were determined by independent t-tests using SPSS 19.0 software.
Results:
Our results showed that NK cell function was significantly downregulated following exposure to pancreatic cancer cells compared to normal pancreatic cells, as demonstrated by lower expressions of activating surface receptors (NKG2D, DNAM-1, NKp30 and NKp46) and cytotoxic granules (Perforin and Granzyme B); decreased secretion of cytokines (TNF-α and IFN-γ); and reduced cytotoxicity against myelogenous leukemia K562 cells. Further investigations revealed that MMP-9 and IDO may be implicated in SW1990 cell-induced NK cell dysfunction by facilitating tumor immune evasion. Blockade by TIMP-1 and/or 1-MT could partially restore NK function.
Conclusions:
Taken together, elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates NK cell dysfunction. Our findings could contribute to the development of NK cell-based immunotherapy in patients with pancreatic cancer.
Insights
Pancreatic cancer cells impair natural killer (NK) cell anti-tumor functions by increasing MMP-9 and IDO. Restoring NK cell activity may improve pancreatic cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Natural killer (NK) cells are crucial for non-specific immune responses in various cancers, including pancreatic cancer.
- NK cell anti-tumor activity diminishes as pancreatic cancer progresses, contributing to tumor immune escape.
- The precise mechanisms of NK cell regulation in pancreatic cancer remain incompletely understood.
Purpose of the Study:
- To investigate the factors contributing to NK cell dysfunction in pancreatic cancer.
- To elucidate the regulatory pathways involved in NK cell-mediated tumor immune escape.
Main Methods:
- In vitro co-culture of NK cells with normal pancreatic ductal cells and pancreatic cancer cell lines.
- Flow cytometry to assess NK cell surface receptors, cytotoxic granules, apoptosis, and cytotoxicity.
- ELISA for cytokine analysis and quantitative RT-PCR for MMP-9, IDO, and COX-2 expression.
- Statistical analysis using independent t-tests.
Main Results:
- Pancreatic cancer cells significantly downregulated NK cell function compared to normal cells.
- Observed reductions in activating receptors, cytotoxic granules, cytokine secretion (TNF-α, IFN-γ), and cytotoxicity.
- MMP-9 and IDO expression in cancer cells were implicated in NK cell dysfunction and immune evasion.
- Blockade of MMP-9 (TIMP-1) and IDO (1-MT) partially restored NK cell function.
Conclusions:
- Elevated MMP-9 and IDO induced by pancreatic cancer cells mediate NK cell dysfunction.
- These findings suggest potential therapeutic targets for enhancing NK cell-based immunotherapy in pancreatic cancer.
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