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Updated: Aug 6, 2026
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
[Therapeutic effects of simultaneous expression of 4-1BBL and sPD-1 on experimental murine hepatoma]
Hui Qiu1, Hui Zhang, Zuo-hua Feng
1Department of Oncology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
Objective:
To explore the possible negative regulatory elements induced by the treatment of experimental murine hepatoma with 4-1BBL, and to investigate the synergistic effects and mechanisms of 4-1BBL and soluble PD-1 (sPD-1) in tumor therapy.
Methods:
Mice were inoculated intramuscularly (i.m.) with 5 x 10(5) H22 tumor cells in the right hind thigh to establish the experimental hepatoma model. The mice were randomly divided into 5 groups (12 mice in each group) after inoculation. The mice of group A, B, C and D were injected with NS, plasmid pcDNA3.1, plasmid p4-1BBL and plasmid pPD-1A respectively. The mice in group E, the combinatorial treatment group, were injected with plasmid p4-1BBL and pPD-1A together. Then the anti-tumor effects, using the tumor growth rates and mice survival rates and others as parameters, were recorded. Meanwhile, the phenotype of lymphocytes and residual tumor cells in the peri-tumor tissue were analyzed.
Results:
Either transfection with 4-1BBL gene alone or with sPD-1 alone could inhibit tumor growth to some extent, but a more significant anticancer effect was obtained in the combinatorial treatment group (group E), in which the tumors were completely inhibited in 42% of the mice, compared with 0 in the other groups. In addition, the survival rate of mice in group E was 100%, compared with 30% in group B, 65% in group C and 62% in group D. The FACS analysis results showed that the expression level of B7-H1 and B7-DC on residual tumor cells in group C (injected with p4-1BBL alone) was higher than that on cells in other groups. The amount of CD8+ T cells in the peri-tumor tissue of group E was significantly increased.
Conclusion:
4-1BBl can induce an up-regulation of negative regulatory elements and at the same time it can enhance the anti-tumor response. The combinatorial treatment with 4-1BBL and sPD-1 can produce a positive synergistic anti-tumor effect on our murine experimental hepatoma.
Insights
This study shows that combining 4-1BBL and soluble PD-1 (sPD-1) therapy significantly enhances anti-tumor effects in murine hepatoma. This combination therapy led to complete tumor inhibition in 42% of mice and improved survival rates, highlighting its therapeutic potential.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Context:
- Hepatocellular carcinoma is a significant global health concern.
- Current therapeutic strategies for hepatoma have limitations.
- Understanding immune regulatory mechanisms is crucial for developing novel cancer therapies.
Purpose:
- To investigate the role of 4-1BB ligand (4-1BBL) in inducing negative regulatory elements in experimental murine hepatoma.
- To evaluate the synergistic anti-tumor effects of combining 4-1BBL with soluble PD-1 (sPD-1) therapy.
- To elucidate the underlying mechanisms of this combined therapeutic approach.
Summary:
- Treatment with 4-1BBL or sPD-1 alone showed moderate inhibition of tumor growth in a murine hepatoma model.
- Combined administration of 4-1BBL and sPD-1 resulted in complete tumor inhibition in 42% of mice and a 100% survival rate.
- The combination therapy significantly increased CD8+ T cell infiltration in the peri-tumor tissue and modulated immune checkpoint molecule expression.
Impact:
- This research demonstrates a potent synergistic anti-tumor effect of combining 4-1BBL and sPD-1.
- The findings suggest a promising novel therapeutic strategy for hepatoma treatment.
- Further investigation into the immune regulatory pathways activated by this combination therapy is warranted.
