黄芪通过下调细胞外基质中βig-h3的表达重塑肿瘤微环境增强免疫检查点抑制剂抗胰腺肿瘤作用及其机制的研究

胰腺癌预后极差，我国传统医学认为“正气不足，邪气踞之”是其发生的重要原因。黄芪因具有“扶正祛邪”的功效，故可改善患者预后。然而其抗肿瘤作用的分子机制尚不明确。申请人前期研究证实，胰腺肿瘤细胞周围缺乏具有细胞毒性的CD8+T细胞。此外，大量的肿瘤相关成纤维细胞（CAFs）和肿瘤相关巨噬细胞（TAMs）富集在肿瘤细胞周围，形成免疫抑制微环境，这是导致胰腺肿瘤对免疫治疗不敏感的根本原因。预实验中，我们发现黄芪通过下调CAFs中PI3K/AKT/NF-κB信号通路，抑制CAFs分泌转化生长因子β诱导蛋白（βig-h3）。既往研究表明βig-h3不但可以抑制CD8+T浸润，还可以增强TAMs的促癌功能。因此我们推测黄芪可能通过下调PI3K信号通路，抑制CAFs分泌βig-h3，重塑肿瘤微环境，从而增强免疫检查点抑制剂抗肿瘤的作用。本研究有望为黄芪联合免疫检查点抑制剂治疗胰腺肿瘤提供理论基础。

The prognosis of pancreatic cancer is extremely poor. Traditional Chinese medicine suggests that “the lack of healthy qi and the presence of pathogenic factors” is the cause of pancreatic cancer. Astragalus can improve the prognosis of pancreatic cancer patients because it has the effect of “strengthening the healthy qi and eliminating the pathogenic factors”. However, the molecular mechanism of the astragalus in the treatment of pancreatic tumors is still unclear. Our previous studies prove that the absence of cytotoxic CD8+T cell infiltration and the presence of immunosuppressive microenvironment, which is composed of tumor-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) are the fundamental reasons that contribute to pancreatic carcinoma; and these lead to pancreatic cancer cells resistant to the traditional therapies and the immune checkpoint inhibitors. In preliminary experiments, we found that astragalus can inhibit the secretion of βig-h3 by CAFs via down-regulating the activity of PI3K/AKT/NF-κB-p65 signaling pathway in CAFs. Astragalus, therefore, can increase the number and function of CD8+T cells in the tumor microenvironment; and astragalus also can relieve the immunosuppressive microenvironment and enhance the anti-carcinoma effect of immune checkpoint inhibitors. This study would support the concept that the combinational therapy, astragalus in combination with immune checkpoint inhibitors could prolong the survival of pancreatic cancer patients.