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Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies
Ken Suzawa1, Kazuhiko Shien1,2, Huang Peng3
1Department of Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Background:
Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and its overexpression by adenovirus vector (Ad-REIC) exhibits a remarkable therapeutic effect on various human cancer types through a mechanism triggered by endoplasmic reticulum stress.
Materials And Methods:
We examined the direct anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma cell lines in vitro, and the distant bystander effect using immunocompetent mouse allograft models with bilateral flank tumors.
Results:
Ad-REIC treatment showed antitumor effect in many lung cancer and malignant mesothelioma cell lines in vitro. In an in vivo model, Ad-REIC treatment inhibited the growth not only of directly treated tumors but also of distant untreated tumors. By immunohistochemical analysis, infiltration of T-cells and natural killer (NK) cells and expression of the major histocompatibility complex (MHC) class I molecules were observed in bilateral tumors.
Conclusion:
Ad-REIC treatment not only had a direct antitumor effect but also an indirect bystander effect through stimulation of the immune system.
Insights
Adenovirus vector-mediated overexpression of the tumor suppressor gene REIC/DKK3 (Ad-REIC) demonstrated direct anti-tumor effects and an indirect bystander effect in lung cancer and mesothelioma models by stimulating the immune system.
Area of Science:
- Oncolytic virotherapy
- Gene therapy
- Immunooncology
Background:
- Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) functions as a tumor suppressor.
- Adenovirus vector-mediated REIC/DKK3 (Ad-REIC) delivery shows therapeutic potential via endoplasmic reticulum stress induction.
Purpose of the Study:
- To evaluate the direct anti-tumor efficacy of Ad-REIC gene therapy.
- To investigate the bystander effect of Ad-REIC in lung cancer and mesothelioma.
- To assess the immunomodulatory impact of Ad-REIC in vivo.
Main Methods:
- In vitro assessment of Ad-REIC on cancer cell lines.
- In vivo evaluation using immunocompetent mouse allograft models with bilateral tumors.
- Immunohistochemical analysis of tumor microenvironment.
Main Results:
- Ad-REIC exhibited direct anti-tumor activity against lung cancer and mesothelioma cell lines in vitro.
- In vivo, Ad-REIC inhibited growth of both directly treated and distant tumors.
- Immunohistochemistry revealed increased T-cell and NK cell infiltration and MHC class I expression in bilateral tumors.
Conclusions:
- Ad-REIC possesses direct anti-tumor capabilities.
- Ad-REIC induces an indirect bystander effect, potentially through immune system stimulation.
- The findings support Ad-REIC as a promising immunogene therapy for solid tumors.
