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Antimetastatic effect of suicide gene therapy for mouse mammary cancers requires T-cell-mediated immune responses
Masa-Aki Shibata1, Junji Morimoto, Kanako Akamatsu
1Department of Anatomy and Cell Biology, Division of Basic Medicine I, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
Abstract:
These experiments were conducted to investigate whether the antimetastatic effects of HSVtk/GCV therapy involve T-cell-mediated immune responses. In the first experiment, immunocompetent syngeneic mice were inoculated with metastatic mammary cancers, then given a direct intratumoral injection of a plasmid vector containing a suicide gene (pHSVtk) or control vector once a week for 8 weeks. Gene electrotransfer treatment was applied to the tumors, and mice were administered ganciclovir (GCV) using a mini-osmotic pump. At the end of the experiment, tumor volume was significantly lower in the pHSVtk/GCV group. Macrophage accumulations were frequently observed in the peripheries of the necrotic regions in pHSVtk-transfected mice. Levels of CD4 and CD8 proteins in tumors were higher in the pHSVtk/GCV group than in the control group. Interleukin (IL)-12 mRNA levels tended to be higher in tumors in the pHSVtk/GCV group, but there were large variations. Tumor microvessel density was significantly lower in the pHSVtk/GCV group. The numbers of dilated lymphatic vessels containing intraluminal tumor cells tended to be higher in the pHSVtk/GCV group. However, vascular endothelial growth factor (VEGF)-A and VEGF-C mRNA levels in tumors were similar in the control and pHSVtk/GCV groups. In the second experiment, tumor volume and metastatic parameters were compared for immunocompetent syngeneic mice and immunodeficient athymic mice (without an intact T-cell system) given pHSVtk/GCV therapy. Although tumor volumes were significantly smaller in both syngeneic and athymic mice given pHSVtk/GCV therapy, the inhibition ratios (relative to control mice) were much greater in syngeneic mice than in athymic mice. No suppression of metastasis to the lymph nodes and lungs was observed for athymic mice given pHSVtk/GCV therapy. Our data suggest that HSVtk/GCV suicide gene therapy exerts an antimetastatic effect via a T-cell-mediated immune response.
Insights
Herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) suicide gene therapy reduces tumor growth and metastasis. This antimetastatic effect is mediated by T-cell immune responses, as shown in immunocompetent mice compared to immunodeficient mice.
Area of Science:
- Oncology
- Immunotherapy
- Gene Therapy
Background:
- Metastatic mammary cancers pose a significant therapeutic challenge.
- Suicide gene therapy, such as HSVtk/GCV, is being explored for cancer treatment.
- The role of the immune system in the antimetastatic effects of HSVtk/GCV therapy requires elucidation.
Purpose of the Study:
- To investigate whether the antimetastatic effects of HSVtk/GCV therapy involve T-cell-mediated immune responses.
- To compare the efficacy of HSVtk/GCV therapy in immunocompetent versus immunodeficient mouse models.
Main Methods:
- Experiment 1: Immunocompetent syngeneic mice with metastatic mammary cancers received intratumoral pHSVtk gene electrotransfer and ganciclovir (GCV).
- Tumor volume, immune cell infiltration (CD4, CD8), cytokine mRNA (IL-12), microvessel density, and lymphatic vessel status were assessed.
- Experiment 2: HSVtk/GCV therapy efficacy was compared between immunocompetent syngeneic mice and immunodeficient athymic mice.
Main Results:
- HSVtk/GCV therapy significantly reduced tumor volume and microvessel density in syngeneic mice, with increased CD4/CD8 T-cell and macrophage infiltration.
- While tumor volume decreased in both syngeneic and athymic mice, the inhibition ratio was significantly higher in syngeneic mice.
- No significant suppression of lymph node or lung metastasis was observed in immunodeficient athymic mice treated with HSVtk/GCV.
Conclusions:
- The antimetastatic effect of HSVtk/GCV suicide gene therapy is dependent on an intact T-cell-mediated immune response.
- HSVtk/GCV therapy demonstrates potential as an immunotherapeutic strategy against cancer metastasis.
