黄芪多糖通过调控T细胞增敏PD-L1阻断剂抗肺腺癌作用的机制初探  

A preliminary investigation of the mechanism of the anti-lung adenocarcinoma effect of astragalus polysaccharide by modulating T cell sensitization of PD-L1 blockers

作　　者：刘海朝 金昱彤 张睿瑄 和仪 边育红 LIU Haizhao;JIN Yutong;ZHANG Ruixuan;HE Yi;BIAN Yuhong(School of Integrative Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China;Department of Pharmacology,Institute of Basic Medical Sciences Chinese Academy of Medical Sciences and School of Basic Medicine Peking Union Medical College,Beijing 100005,China)

机构地区：[1]天津中医药大学中西医结合学院,天津301617 [2]中国医学科学院基础医学研究所北京协和医学院基础学院药理系,北京100005

出　　处：《现代肿瘤医学》2024年第9期1573-1580,共8页Journal of Modern Oncology

基　　金：国家自然科学基金资助项目(编号:82374320,81573707);天津中医药大学研究生科研创新项目(编号:YJSKC-20231005);天津中医药大学中西医结合学院研究生创新基金项目(编号:ZXYCXLX202206)。

摘　　要：目的:观察黄芪多糖联合PD-L1阻断剂对Lewis肺腺癌小鼠皮下肿瘤生长的影响,初步探讨基于肿瘤免疫微环境,黄芪多糖促进T细胞的增殖,增敏PD-L1阻断剂治疗肺腺癌可能的作用机制。方法:建立Lewis肺腺癌荷瘤小鼠模型,造模后给予黄芪多糖联合PD-L1阻断剂治疗,同时分别设置二者单独用药组。给药结束后计算抑瘤率,脾指数及胸腺指数;HE染色观察小鼠肿瘤组织病理变化;流式细胞术检测外周血中CD4^(+)、CD8^(+)T细胞比率;免疫荧光法检测T细胞浸润情况;ELISA法检测肿瘤组织中促炎因子IL-1β、IL-6及TNF-α的水平,Western Blot法检测肿瘤组织中IL-10以及TGF-β的蛋白表达。结果:与模型组相比,黄芪多糖联合PD-L1阻断剂组可显著增加荷瘤小鼠体重,减轻肿瘤重量,上调脾指数及胸腺指数,抑制肿瘤生长;同时,黄芪多糖联合PD-L1阻断剂组可显著上调小鼠外周血中CD4^(+)T细胞(CD3^(+)CD4^(+))比率及CD4^(+)/CD8^(+)T细胞(CD3^(+)CD4^(+)/CD3^(+)CD8^(+))比值,增加肿瘤组织中CD4^(+)和CD8^(+)T细胞的浸润,促进小鼠肿瘤组织中促炎细胞因子IL-1β、IL-6及TNF-α的分泌,降低免疫抑制因子IL-10及TGF-β的表达。结论:黄芪多糖联合PD-L1阻断剂对Lewis肺腺癌小鼠有较好的抗肿瘤效果,黄芪多糖可通过改善肿瘤免疫微环境,增加肿瘤组织中T细胞的浸润,发挥增敏PD-L1阻断剂抗肺腺癌的作用。Objective:To observe the effect of astragalus polysaccharide combined with PD-L1 blocker on subcutaneous tumor growth in Lewis lung adenocarcinoma mice,and to preliminarily explore the possible mechanism of action of astragalus polysaccharide to promote the proliferation of T-cells based on the tumor immune microenvironment and to sensitize the PD-L1 blocker for the treatment of lung adenocarcinoma.Methods:Lewis lung adenocarcinoma mouse model was established,and after modeling,astragali polysaccharide combined with PD-L1 blocker was given to treat the tumor,while the two alone groups were set up separately.The tumor inhibition rate,spleen index and thymus index were calculated at the end of drug administration.HE staining was used to observe the pathological changes of tumor tissues.Flow cytometry was used to detect the ratio of CD4^(+)and CD8^(+)T cells in the peripheral blood.Immunofluorescence was used to detect the infiltration of T cells.The levels of the pro-inflammatory factors IL-1β,IL-6,and TNF-αwere detected by ELISA in the tumor tissues.IL-10 and TGF-βprotein expression in tumor tissues by Western Blot.Results:Compared with the model group,astragalus polysaccharide combined with PD-L1 blocker group could significantly increase the body weight of the loaded mice,reduce the tumor weight,up-regulate the splenic index and thymic index,and inhibit the tumor growth.At the same time,the astragalus polysaccharide combined with PD-L1 blocker group could significantly increase the ratio of CD4^(+)T cells(CD3^(+)CD4^(+))and the ratio of CD4^(+)/CD8^(+)T cells(CD3^(+)CD4^(+)/CD3^(+)CD8^(+))ratio,enhanced the infiltration of CD4^(+)and CD8^(+)T cells in tumor tissues,promoted the secretion of pro-inflammatory cytokines IL-1β,IL-6,and TNF-α,and decreased the expression of immunosuppressive factors IL-10 and TGF-βin tumor tissues of mice.Conclusion:Astragali polysaccharide combined with PD-L1 blocker has a better anti-tumor effect on Lewis lung adenocarcinoma mice.Astragali polysaccharide can exert the anti-tu

关 键 词：黄芪多糖 PD-L1阻断剂 肺腺癌 细胞因子 肿瘤免疫微环境 

分 类 号：R734.2[医药卫生—肿瘤]