六味地黄丸通过GJIC介导抗原交叉递呈激活肿瘤自杀基因疗法免疫杀伤的作用

Suicide gene therapy is currently one of the most promising new approaches to cancer treatment, and the bystander effect may clear tumor cells that do not carry suicide genes to enhance the therapeutic effect. Preliminary studies have shown that traditional Chinese medicine Liuwei Dihuang Wan has a synergistic effect on the mice transplanted tumors suicide gene therapy(liver cancer and melanoma). Immune mechanism is the most important mechanism of bystander effect. Whether the synergistic effect of Liuwei Dihuang Wan is related to the immune mechanism is an important scientific issue that requires further study. During the study on the mechanism of "gap junction" synergistic effect of Liuwei Dihuang Wan, we found that this and its active components can upregulate the expression of connexins in tumor cells and enhance the function of gap junction intercellular communication(GJIC). Many articles have reported that gap junction intercellular communication can be associated with antigen cross-presentation. Cross-presentation of tumor antigens is a key step in tumor immune activation. However, most tumor cells have GJIC dysfunction, which may affect the activation of anti-tumor immunity and impair the immune mechanism of the bystander effect. Liuwei Dihuang Wan and its active ingredients can upregulate GJIC function of tumor cells, which suggests that it may promotes the cross-presentation of tumor antigens, thereby activating CD8+ T cells and enhancing the immune-killing effect. This study intends to explain the mechanism of Liuwei Dihuang Pill's synergistic effect on tumor suicide gene therapy from the perspective of immune mechanism in vitro and in vivo.

自杀基因疗法因旁杀伤效应能清除未转染基因的肿瘤细胞而成为最具前景的肿瘤治疗新方法。前期研究表明滋阴补肾经方六味地黄丸对小鼠移植性肿瘤自杀基因治疗具有增效作用。免疫机制是旁杀伤效应中最重要的机制。六味地黄丸的增效作用是否与免疫机制相关是需要进一步研究的重要科学问题。在对六味地黄丸增效作用的缝隙连接机制研究过程中，发现该方及其活性成分能上调肿瘤细胞缝隙连接蛋白表达，并增强缝隙连接通讯（GJIC）功能。大量文献报导，GJIC功能与抗原交叉递呈相关。肿瘤抗原的交叉递呈是肿瘤免疫激活的关键步骤。但大多数肿瘤细胞存在GJIC功能低下，可能会影响抗肿瘤免疫的激活，削弱旁杀伤效应的免疫机制。六味地黄丸及其活性成分能上调肿瘤细胞GJIC功能，提示该方可促进肿瘤抗原的交叉递呈，激活CD8+T细胞，增强免疫杀伤效应。本课题拟通过体内、外实验，从免疫机制角度阐释六味地黄丸对肿瘤自杀基因疗法增效的作用机制。

自杀基因疗法因旁杀伤效应能清除未转染基因的肿瘤细胞而成为最具前景的肿瘤治疗新方法。前期研究表明滋阴补肾经方六味地黄丸对小鼠移植性肿瘤自杀基因治疗具有增效作用。免疫机制是旁杀伤效应中最重要的机制。六味地黄丸的增效作用是否与免疫机制相关是需要进一步研究的重要科学问题。在对六味地黄丸增效作用的缝隙连接机制研究过程中，发现该方及其活性成分能上调肿瘤细胞缝隙连接蛋白表达，并增强缝隙连接通讯（GJIC）功能。大量文献报导，GJIC功能与抗原交叉递呈相关。肿瘤抗原的交叉递呈是肿瘤免疫激活的关键步骤。但大多数肿瘤细胞存在GJIC功能低下，可能会影响抗肿瘤免疫的激活，削弱旁杀伤效应的免疫机制。六味地黄丸及其活性成分能上调肿瘤细胞GJIC功能，提示该方可促进肿瘤抗原的交叉递呈，激活CD8+T细胞，增强免疫杀伤效应。本课题拟通过体内、外实验，从免疫机制角度阐释六味地黄丸对肿瘤自杀基因疗法增效的作用机制。