Dioscin potentiates the antitumor effect of suicide gene therapy in melanoma by gap junction intercellular communication-mediated antigen cross-presentation

• Published in: Biomedicine & pharmacotherapy Vol. 150; p. 112973
• Main Authors: Zhang, Wenbo, Lin, Lingyun, Zhang, Yujian, Zhao, Tingxiu, Zhan, Yujuan, Wang, Huiqi, Fang, Junfeng, Du, Biaoyan
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-06-2022; Elsevier
• Subjects: Antigen cross-presentation; Dioscin; Gap junction intercellular communication; Immunoregulation; Melanoma; Suicide gene therapy; Suicide gene therapy; Gap junction intercellular communication; Dioscin; Antigen cross-presentation; Immunoregulation; Melanoma
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.112973

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.
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•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.