Dioscin potentiates the antitumor effect of suicide gene therapy in melanoma by gap junction intercellular communication-mediated antigen cross-presentation - 27/05/22
Abstract |
Dioscin (Dio), steroid saponin, exists in several medicinal herbs with potent anticancer efficacy. This study aimed to explore the effect of Dio on the immune-related modulation and synergistic therapeutic effects of the herpes simplex virus thymidine kinase/ganciclovir (HSV-Tk/GCV) suicide gene therapy system in murine melanoma, thereby providing a research basis to improve the potential immunomodulatory mechanism underlying combination therapy. Using both in vitro and in vivo experiments, we confirmed the immunocidal effect of Dio-potentiated suicide gene therapy on melanoma. The results showed that Dio upregulated connexin 43 (Cx43) expression and improved gap junction intercellular communication (GJIC) in B16 cells while increasing the cross-presentation of antigens by dendritic cells (DCs), eventually promoting the activation and antitumor immune killing effects of CD8+ T lymphocytes. In contrast, inhibition or blockade of the GJIC function (overexpression of mutant Cx43 tumor cells/Gap26) partially reversed the potentiating effect. The significant synergistic effect of Dio on HSV-Tk/GCV suicide gene therapy was further investigated in a B16 xenograft mouse model. The increased number and activation ratio of CD8+ T lymphocytes and the levels of Gzms-B, IFN-γ, and TNF-α in mice reconfirmed the potential modulatory effects of Dio on the immune system. Taken together, Dio targets Cx43 to enhance GJIC function, improve the antigens cross-presentation of DCs, and activate the antitumor immune effect of CD8+ T lymphocytes, thereby providing insights into the potential immunomodulatory mechanism underlying combination therapy.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Dioscin synergistically functioned with suicide gene therapy for melanoma in mice. |
• | Dioscin targeted Cx43 to improve GJIC of B16 cells. |
• | Dioscin-mediated GJIC promoted antigen cross-presentation of DCs. |
Keywords : Dioscin, Melanoma, Suicide gene therapy, Gap junction intercellular communication, Antigen cross-presentation, Immunoregulation
Plan
Vol 150
Article 112973- juin 2022 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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