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Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
Non-ablative focused ultrasound induces an adaptive immune response to suppress pancreatic cancer: a preclinical
Eun-Joo Park1,2,3, Yundeok Ahn1, Yuri Cheon1
1Department of Radiology, Seoul National University Hospital, Seoul, Korea.
Purpose:
This study aimed to investigate whether, and by what mechanisms, focused ultrasound-mediated mechanical stimulation (MS) can induce anti-tumor immunity and elicit an abscopal effect in a pancreatic cancer model.
Methods:
In study 1, animals bearing unilateral murine pancreatic tumors (Pan02) in the flank were divided into five groups according to the single or combined use of gemcitabine (Gem), thermal ablation, or MS. Study 2 was conducted in mice bearing bilateral flank tumors to evaluate abscopal effects. Tumor growth suppression, tissue damage, expression of tumor growth-inhibitory genes and cytokines, and anti-tumor cytotoxic T lymphocyte responses were analyzed.
Results:
In study 1, the MS+Gem group exhibited significantly higher levels of interleukin-6, KC-GRO, and tumor necrosis factor-α; higher proportions of CD8+ cells and granzyme B (GrB); and lower Foxp3 expression than the other groups. A significantly higher ratio of CD8+ cells among tumor-infiltrating lymphocytes (TIL) was also observed in the MS+Gem group (P<0.005 at week 2). In study 2, significant growth suppression of the untreated contralateral tumor was observed in the MS+Gem group. Immune analysis of the untreated tumor showed significantly higher proportions of CD8+ cells and GrB, along with a lower proportion of Foxp3+ cells, in the MS+Gem group. The MS+Gem group also demonstrated a higher CD8+/TIL ratio in the untreated tumor.
Conclusion:
MS+Gem effectively suppressed tumor growth, promoted apoptosis-related factors, and enhanced intratumoral infiltration of cytotoxic T cells in treated tumors. In addition, MS+Gem induced an abscopal effect in untreated tumors, suggesting its potential to mediate systemic anti-tumor immune responses in pancreatic cancer treatment.
Insights
Focused ultrasound mechanical stimulation combined with gemcitabine enhances anti-tumor immunity and suppresses pancreatic tumors. This combination therapy also triggers an abscopal effect, reducing untreated tumor growth and boosting systemic immune responses.
Area of Science:
- Oncology
- Immunology
- Biomedical Engineering
Background:
- Pancreatic cancer remains a significant health challenge with limited effective treatment options.
- Developing novel therapeutic strategies to enhance anti-tumor immunity is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the potential of focused ultrasound-mediated mechanical stimulation (MS) to induce anti-tumor immunity.
- To evaluate the abscopal effect of MS in combination with gemcitabine (Gem) in a pancreatic cancer model.
Main Methods:
- Murine pancreatic tumors (Pan02) were treated with gemcitabine, thermal ablation, or MS, individually or in combination.
- Bilateral flank tumors were used to assess abscopal effects.
- Tumor growth, tissue damage, gene expression, and cytotoxic T lymphocyte responses were analyzed.
Main Results:
- The MS+Gem group showed significantly increased levels of pro-inflammatory cytokines (IL-6, KC-GRO, TNF-α).
- Enhanced infiltration of CD8+ cytotoxic T cells and Granzyme B (GrB) was observed, with reduced Foxp3+ regulatory T cells.
- Significant suppression of untreated tumor growth (abscopal effect) was noted in the MS+Gem group, with similar immune profile changes.
Conclusions:
- MS combined with gemcitabine effectively suppresses pancreatic tumor growth and promotes apoptosis-related factors.
- This combination therapy enhances intratumoral cytotoxic T cell infiltration and induces a systemic abscopal effect.
- MS+Gem demonstrates potential for mediating systemic anti-tumor immune responses in pancreatic cancer treatment.
