REIC/Dkk-3 Gene Therapy Induces Immunogenic Cell Death in a Mouse Model of Malignant Mesothelioma

Background/ Aim: The adenovirus vectorcarrying reduced expression in immortalized cell (REIC) gene (Ad-REIC) increases endoplasmic reticulum stress chaperone GRP78/BiP expression and induces the JNK-mediated apoptotic pathway. We aimed to determine whether Ad-REIC-induced apoptotic cell death can trigger immunogenic cell death (ICD). Materials and Methods: We examined the emission of damage-associated molecular patterns in vitro and the vaccination effect in vivo. We determined the immunological changes in the tumour microenvironment by putative ICD inducers and the combined effects of immune checkpoint blockade therapies. Results: Ad-REIC induced the release of high-mobility group box 1 and adenosine triphosphate and the translocation of calreticulin in murine mesothelioma AB12 cells. The vaccination effect was elicited by Ad-REIC treatment in vivo. The effect of Ad-REIC was potentiated by anti-cytotoxic Tlymphocyte-associated protein 4 antibody treatment in a murine mesothelioma AB1-HA cell model. Conclusion: AdREIC induces ICD in malignant mesothelioma.

Automated summary

The study demonstrates that Ad-REIC can induce apoptotic cell death in malignant mesothelioma cells and trigger immunogenic cell death. In vivo experiments showed that Ad-REIC induced the release of damage-associated molecular patterns and exhibited a vaccination effect. Furthermore, the efficacy of Ad-REIC was further enhanced when combined with immune checkpoint blockade therapies.