Department of Pathology and Pathophysiology, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
Biomed Pharmacother. 2022 Jun;150:112973. doi: 10.1016/j.biopha.2022.112973. Epub 2022 Apr 22.
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.
薯蓣皂苷元（Dio）是一种甾体皂苷，存在于多种具有强大抗癌功效的药用植物中。本研究旨在探讨 Dio 对单纯疱疹病毒胸苷激酶/更昔洛韦（HSV-Tk/GCV）自杀基因治疗系统的免疫相关调节作用及其协同治疗效果的影响，为提高联合治疗的潜在免疫调节机制提供研究依据。通过体内外实验，我们证实了 Dio 增强自杀基因治疗对黑色素瘤的免疫杀伤作用。结果表明，Dio 上调 B16 细胞连接蛋白 43（Cx43）表达，增强缝隙连接细胞间通讯（GJIC），同时增加树突状细胞（DCs）的抗原交叉呈递，进而促进 CD8 T 淋巴细胞的激活和抗肿瘤免疫杀伤作用。相反，抑制或阻断 GJIC 功能（过表达突变型 Cx43 肿瘤细胞/Gap26）部分逆转了增强作用。我们进一步在 B16 异种移植小鼠模型中研究了 Dio 对 HSV-Tk/GCV 自杀基因治疗的显著协同作用。CD8 T 淋巴细胞数量和激活率的增加以及 Gzms-B、IFN-γ和 TNF-α水平的增加，再次证实了 Dio 对免疫系统的潜在调节作用。总之，Dio 通过靶向 Cx43 增强 GJIC 功能，改善 DCs 的抗原交叉呈递，激活 CD8 T 淋巴细胞的抗肿瘤免疫效应，为联合治疗的潜在免疫调节机制提供了新的见解。
