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Effect of Flt3 ligand gene transfer in experimental pancreatic cancer
E Ryschich1, G Huszty, N Wentzensen
1Dept. of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
Background:
Fms-like tyrosine kinase 3 receptor (Flt3) is an important receptor expressed on the cell membrane of immature antigen-presenting cells. The binding of Flt3 to its ligand (FL) activates the proliferation of dendritic cells (DCs). This mechanism is currently being evaluated in the therapy of malignant tumors. The aim of the present study was to study the effect of FL gene transfer on the immune response and tumor growth in experimental pancreatic cancer.
Materials And Methods:
The rat FL was sequenced and cloned from total mRNA extract of the spleen. Transfection efficiency of subcutaneously growing rat duct-like pancreatic cancer (DSL6A) with DOTAP-/cholesterol-based liposomes was tested using a pcDNA3.1-lacZ construct. Flt3 ligand production of in vitro transfected tumor cells and in vivo transfected tumors was measured by enzyme-linked immunosorbent assay. Tumor induction was achieved in Lewis rats by a subcutaneous inoculation of syngeneic pancreatic tumor cells (DSL6A). The animals were allocated into three groups: control, mock treatment, and treatment with FL plasmid. The plasmid was injected intratumorally three times per week for 2 weeks. The total observation time was 6 weeks.
Results:
The tumor volume was significantly lower in the FL-transfected group during the first 3 weeks. The number of responders was significantly higher in the FL group compared with control and mock treatment. The number of CD80+ DCs in the spleen was significantly higher after FL gene transfer. The responders showed a significantly higher number of splenic natural killer (NK) cells. There were no differences of infiltrating lymphocytes, proliferation, and tumor blood vessels between the groups.
Conclusion:
Intratumoral gene transfer of FL in rats activated proliferation of DCs and NK cells, which causes a moderate reduction of tumor growth. This improvement of local tumor control during the first weeks could be explained by an improved antigen presentation.
Insights
Gene transfer of Fms-like tyrosine kinase 3 receptor ligand (FL) into pancreatic tumors activated dendritic cells (DCs) and natural killer (NK) cells. This immune response moderately reduced tumor growth in rats during the initial weeks.
Area of Science:
- Immunology
- Oncology
- Gene Therapy
Background:
- Fms-like tyrosine kinase 3 receptor (Flt3) binding to its ligand (FL) promotes dendritic cell (DC) proliferation.
- This mechanism is being explored for cancer therapy.
- The study investigates FL gene transfer's impact on immune response and tumor growth in pancreatic cancer.
Purpose of the Study:
- To evaluate the effect of FL gene transfer on the immune system and tumor progression in a rat model of pancreatic cancer.
Main Methods:
- Rat FL gene was cloned and delivered via liposomes into pancreatic tumors.
- Tumor growth, immune cell populations (DCs, NK cells), and related markers were assessed over 6 weeks.
- Animals were divided into control, mock treatment, and FL gene transfer groups.
Main Results:
- FL gene transfer led to a significant reduction in tumor volume within the first 3 weeks.
- Increased numbers of splenic CD80+ dendritic cells and natural killer cells were observed in the FL group.
- A higher proportion of responders with enhanced immune cell activity was noted compared to controls.
Conclusions:
- Intratumoral FL gene transfer effectively activates dendritic cells and NK cells.
- This activation results in a moderate decrease in tumor growth and improved local tumor control.
- Enhanced antigen presentation is suggested as the mechanism for improved tumor control.
