枸杞多糖LBP3通过靶向树突状细胞代谢逆转肿瘤耐抗PD-1单抗治疗的机制

Recent studies have shown that tumor microenvironment changes dendritic cell (DCs) metabolism and affects their differentiation and maturation, which is an important reason for tumor resistance to anti-PD-1 monoclonal antibody therapy. The maturation of dendritic cell can be promoted by targeting metabolism in-situ of tumor tissue, which has synergistic effect with PD-1 mAb in the melanoma tumor. Lycium barbarum polysaccharide can promote maturation of DCs from bone marrow in vitro and tumor tissue in vivo. In the preliminary study of present project, we established a mouse hepatocellular carcinoma transplantation tumor model that was resistant to anti-PD-1 mAb therapy. We found that LBP3 from lycium barbarum polysaccharide with intellectual property rights has reversed tumor resistance to anti-PD-1 mAb therapy and promoted the maturation of DCs in vitro. Thus, we hypothesize that LBP3 reverses tumor resistance to anti-PD-1 mAb therapy by targeting the dendritic cells metabolism in tumor tissues. We will continue to investigate the effects of LBP3 on the function of tumor infiltrating T cells and DCs in the drug-resistant mice. The metabolic pathway that LBP3 promote the maturation of DCs will be screened in vitro experiment using the proteomics and metabolomics techniques, and verified in drug resistant mouse models. Finally, the mechanism of LBP3 reverses tumor resistance to anti-PD-1 mAb therapy by targeting dendritic cell metabolism will be demonstrated by using DCs immunodeficiency mice and pathway inhibitor which targets the metabolic pathway. The results will provide the traditional Chinese medicine therapy strategies for tumor resistance to anti-PD-1 mAb therapy.

最新的研究表明肿瘤微环境使树突状细胞（DCs）代谢改变而影响细胞分化、成熟是肿瘤耐抗PD-1单抗治疗重要原因之一，原位靶向肿瘤组织DCs代谢促进其成熟在协同PD-1单抗治疗黑色素瘤中有增效作用。枸杞多糖可以促进骨髓来源DCs体外成熟和肿瘤组织DCs成熟；本课题前期发现枸杞多糖LBP3具有逆转肿瘤耐抗PD-1单抗治疗的药效，并在体外促进DCs成熟。故提出假说：LBP3可以通过靶向肿瘤组织DCs代谢逆转肿瘤耐抗PD-1单抗治疗。本课题将继续检测LBP3对耐药小鼠肿瘤浸润T细胞、DCs功能的影响；利用DCs体外培养实验结合蛋白组学和代谢组学技术筛选LBP3促进DCs成熟的代谢通路，并在耐药小鼠模型上加以验证；最后采用DCs免疫缺陷小鼠和通路抑制剂干预DCs代谢通路的方法验证LBP3通过靶向DCs代谢通路逆转肿瘤耐抗PD-1单抗治疗的机制。结果为解决肿瘤耐抗PD-1单抗治疗提供中医药策略。