基于Akt通路研究甘遂半夏汤抑制肝癌MDSCs的药效物质基础及其作用机制

髓源性抑制细胞（MDSCs）是参与肝癌免疫耐受发生、发展的关键细胞成分，机制包括抑制T细胞和NK细胞功能，诱导Tregs扩增，促进巨噬细胞程序性死亡受体表达等，与肝癌不良预后密切相关。项目前期研究发现，MDSCs浸润程度随着肝癌进展而逐渐增高，甘遂半夏汤提取物具有下调肝癌细胞PI3K/Akt信号通路，减少脾脏及肿瘤组织中MDSCs浸润，调节淋巴细胞的功能。研究证实Akt是MDSCs分化和生存的“核心激酶”。我们结合前期研究结果及文献报道，推测甘遂半夏汤中具有抑制MDSCs分化和增殖的活性物质，本课题拟结合活性导向的UPLC-Q/TOF快速筛选平台辨析抑制MDSCs分化和功能的有效成分，以化学生物学手段标记的关键成分进行靶点垂钓，揭示靶点-通路的关联，探析药效分子的作用机制，明确药效物质组与靶标群的相关效应，为揭示中药复方免疫调节治疗肿瘤的科学内涵及临床药物开发提供参考。

Myeloid-derived suppressor cells (MDSCs) are involved in the progression and the immune tolerance of liver cancer. The mechanisms include inhibiting the function of T cells and NK cells, inducing the expansion of Tregs, promoting the expression of PD-L1 in macrophages, and closely relating to poor prognosis of liver cancer. We found that the degree of MDSCs infiltration gradually increased with the progress of hepatocellular carcinoma. Gansui Banxia Decoction Extracts have effects on down-regulation of the PI3K/Akt signaling pathway, reducing MDSCs in the spleen and tumor tissues, and regulation of lymphocyte function. Studies have confirmed that Akt is the "core of kinase-regulated interactomes" for MDSC differentiation and activation. Thus, we aim to finding the active ingredients that inhibiting of PI3K/Akt pathway to regulate MDSC function and reducing the activation of downstream target genes of MDSC. However, the active substances and mechanisms are unknown. We intend to track the active substances, establish a technology for finding compounds based on UPLC-Q/TOF analysis to find active ingredients with the function of regulating MDSC, and analyze the mechanisms of regulation of the MDSCs function. The related research may provide new experimental evidence for the mechanism of reducing tumor immune tolerance of Gansui Banxia Decoction in development of liver cancer, and provides a reference for revealing the scientific connotation of Chinese medicine compound's immune regulation.