基于NF-κB通路介导的重塑肿瘤微环境探索黄芪联合PD-1抑制剂对PD-1人源化小鼠抑瘤作用的影响与机制研究

In recent years, immunotherapy represented by PD-1 inhibitors has made breakthroughs in lung cancer and various malignant tumors. Its mechanism of killing tumors by restoring the ability of the body's autoimmune system conforms to the concept of "nourishing positive accumulation and eliminating cancer by itself". Astragalus membranaceus （HQ）, as a representative herb of strengthening the body, is widely controversial and concerned whether it can be combined with PD-1. Exploring the interaction between HQ and PD-1 based on tumor microenvironment (TME) is a research hotspot and direction. In theory, TCM considers that TME is essentially spleen deficiency, and HQ is an important tonic for spleen-qi. In clinical practice, PD-1 combined with TME-related anti-vascular, dendritic cells (DC) and IL-12 can significantly improve the efficacy. Previous studies in our team showed that HQ compound combined with auto-amplified DC and chemotherapy can prolong the overall survival time of advanced non-small cell lung cancer (NSCLC) with negative driving genes by more than one time. The hypothesis of HQ synergistic immunotherapy based on remodeling TME and NF-κB pathway to promote DC function and IL-12 was put forward. The effects of HQ on anti-tumor effect of PD-1 in mice bearing lung cancer in vivo and mutuDC cells knocked out of NF-κB in vitro were studied for the first time. To clarify its molecular mechanism and pathway，and provide scientific evidence for clinical application of combined immunotherapy with Traditional Chinese Medicine.

近年来以PD-1抑制剂为代表的免疫治疗在肺癌等肿瘤取得突破进展，其通过恢复机体自身免疫系统能力实现肿瘤杀伤的机制符合中医“养正积自除”的理念。黄芪作为扶正类代表药物，能否与PD-1联用广受争议与关注，基于肿瘤微环境（TME）探讨其相互影响是研究热点与探索方向。理论认识上，中医认为TME本质为脾虚，黄芪为补益脾气要药；临床实践中，PD-1联合与TME相关的抗血管、树突状细胞（DC）和IL-12等均显著提高疗效，本团队前期研究显示黄芪复方联合自体扩增DC及化疗可延长驱动基因阴性晚期非小细胞肺癌总生存时间1倍以上；据此我们提出黄芪基于重塑TME及NF-κB通路促进DC功能与IL-12而协同免疫治疗的假说，首次应用PD-1人源化肺癌荷瘤小鼠体内研究与敲除NF-κB的MutuDC细胞体外研究，明确黄芪对PD-1抗肿瘤作用的影响，阐明其分子机制与通路，为中医联合免疫治疗的临床应用提供科学证据。

PD-1抑制剂在肿瘤中广泛应用，其通过恢复机体身免疫系统能力实现肿瘤杀伤的机制符合中医“养正积自除”的理念。黄芪作为扶正类代表药物 ，能否与PD-1联用广受争议与关注，基于肿瘤微环境（TME）探讨其相互影响是研究热点与探 索方向。理论认识上，中医认为TME本质为脾虚，黄芪为补益脾气要药；临床实践中，PD-1联 合与TME相关的抗血管、树突状细胞（DC）和IL-12等均显著提高疗效，本团队前期研究显示黄芪复方联合自体扩增DC及化疗可延长驱动基因阴性晚期非小细胞肺癌总生存时间1倍以上。据此此课题试图回答黄芪是否基于重塑TME及NF-κB通路促进DC功能与IL-12而协同免疫治疗。.项目通过 PD-1人源化荷瘤小鼠体内实验，明确联合应用黄芪对PD-1抑制剂抗肿瘤作用的影响；通过体外实验并进一步阐述黄芪对肿瘤微环境的影响及通过NF-κB通路调节DC与IL-12进而影响PD-1抑制剂疗效的机制。结果表明：联合应用黄芪提高了PD-1抑制剂在PD-1人源化肺癌小鼠中的抗肿瘤作用。且机制研究发现黄芪可能通过降低HIF-1α、VEGF，改善肿瘤微血管密度，调节肿瘤组织慢性炎症微环境；同时提高增殖CD8+T细胞，同时降低Treg细胞数量，从而改善肿瘤免疫抑制微环境，协同PD-1抑制剂发挥抗肿瘤作用。可见黄芪可能通过调节肿瘤炎症微环境及免疫抑制微环境，从而改善肺癌肿瘤微环境，协同免疫检查点抑制剂发挥抗肿瘤作用，为临床在肿瘤免疫治疗期间辨证使用中药提供了科学依据。

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