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芪珍汤介导DC细胞成熟激活IL-12/JAK2/STAT4通路使PD-1抑制剂增敏治疗结直肠癌的机制研究

Mechanism of Qizhen decoction-mediated maturation of DC cells to activate the IL-12/JAK2/STAT4 pathway to sensitise PD-1 inhibitors in the treatment of colorectal cancer.

发表日期:2023 Nov 11
作者: Xianbin Kong, Qingbo Li, Dong Wang, Miao Wang, Fan Yang, Jingyan Meng
来源: JOURNAL OF ETHNOPHARMACOLOGY

摘要:

传统中药已被用来治疗结直肠癌(CRC)。芪珍汤(QZD)是一种潜在的中药复方,具有多种生物活性。临床已用于治疗结直肠癌,并被证明有效。探讨肠道菌群支持的QZD联合PD-1抑制剂对结直肠癌的影响,并阐明QZD增强敏感性的机制PD-1抑制剂抗结直肠癌的作用。肠道菌群介导QZD联合PD-1抑制剂治疗结直肠癌的效果观察。我们采用流式细胞术和qPCR检测QZD联合PD-1抑制剂对结直肠癌野生小鼠模型中效应T细胞激活的影响。在野生和无菌小鼠模型中,观察炎症因子、病理变化、体重、结直肠长度和肿瘤负荷的差异。在QZD联合PD-1抑制剂治疗结直肠癌的机制研究中,研究评估了各组小鼠中Akkermansia的丰度、效应T细胞和DC细胞的表型以及炎症因子,以评估QZD联合PD-1抑制剂治疗结直肠癌的作用机制。确定 Akkermansia 是否在激活 DC 细胞中发挥作用。基于JAK2/TYK2/STAT4通路,进一步研究了QZD对结直肠癌PD-1抑制剂增敏的机制。我们发现QZD联合PD-1抑制剂可以通过诱导更关键的免疫反应来提高对结直肠癌的治疗效果。功能。 QZD 促进肠道内阿克曼氏菌丰度的增加。 Akkermansia 促进 DC 细胞成熟,成熟 DC 细胞激活 IL-12/JAK2/STAT4 通路,从而显着激活效应 T 细胞。 Akkermansia是QZD联合PD-1抑制剂介导的免疫对结直肠癌发挥治疗作用的关键。QZD增敏PD-1抑制剂的作用机制是促进DC细胞成熟释放IL-12并激活JAK2/STAT4 途径通过增加 Akkermansia 的丰度来诱导效应 T 细胞激活。版权所有 © 2023。由 Elsevier B.V 出版。
Traditional Chinese medicine has been utilized to treat colorectal cancer (CRC). Qizhen decoction (QZD), a potential compound prescription of traditional Chinese medicine, possesses multiple biological activities. It has been used to treat CRC in clinical practice and has been proven to be effective.To investigate the impact of QZD supported by intestinal flora in combination with PD-1 inhibitor on colorectal cancer, and to elucidate the mechanism by which QZD enhances the sensitivity of PD-1 inhibitor against colorectal cancer.Observation of Intestinal Flora Mediating the Effect of QZD Combined with PD-1 Inhibitor in the Treatment of Colorectal Cancer. We used Flow cytometry and qPCR to detect the effect of QZD combined with PD-1 inhibitor on the activation of effector T cells in a wild mouse model of colorectal cancer. In wild and germ-free mouse models, the differences in inflammatory factors, pathological change, body mass, colorectal length, and tumour load were observed. In the study of the mechanism of QZD combined with PD-1 inhibitor in the treatment of colorectal cancer, the study evaluated the abundance of Akkermansia, the phenotypes of effector T cells and DC cells, as well as inflammatory factors in each group of mice to determine whether Akkermansia played a role in activating DC cells. Based on the JAK2/TYK2/STAT4 pathway, the mechanism of PD-1 inhibitor sensitisation by QZD in colorectal cancer was further investigated.We found that QZD combined with PD-1 inhibitor could improve the therapeutic effect on colorectal cancer by inducing more critical immune functions. QZD promotes increased Akkermansia abundance in the gut. Akkermansia promotes maturation of DC cells, and mature DC cells activate the IL-12/JAK2/STAT4 pathway, which significantly activates effector T cells. Akkermansia is key to QZD combined with PD-1 inhibitor-mediated immunity exerting a therapeutic effect on colorectal cancer.The mechanism of action of the QZD sensitizing PD-1 inhibitor is to promote the maturation of DC cells to release IL-12 and activate the JAK2/STAT4 pathway to induce effector T cell activation by increasing the abundance of Akkermansia.Copyright © 2023. Published by Elsevier B.V.