双特异性anti-PD-L1&CXCR4纳米抗体联合吉西他滨协同PBMC对胰腺癌治疗作用的探究  

Therapeutic effect of anti-PD-L1&CXCR4 bispecific nanobody combined with gemcitabine in synergy with PBMC on pancreatic cancer treatment

作　　者：胡海 徐舒怡 郑玥江 朱建伟 吴明媛 HU Hai;XU Shu-yi;ZHENG Yue-jiang;ZHU Jian-wei;WU Ming-yuan(Engineering Research Center of Cell&Therapeutic Antibody,Ministry of Education,School of Pharmacy,Shanghai Jiao Tong University,Shanghai 200240,China)

机构地区：[1]上海交通大学药学院,细胞工程及抗体药物教育部工程研究中心,上海200240

出　　处：《药学学报》2025年第2期388-396,共9页Acta Pharmaceutica Sinica

摘　　要：胰腺癌是一种高度恶性的肿瘤,生存率低,预后极差。一线化疗药物吉西他滨单药治疗效果有限,但在杀伤肿瘤细胞的同时可以活化树突状细胞,促进抗原提呈,提高肿瘤对免疫疗法的敏感性。免疫疗法在肿瘤治疗中取得了一定进展,但程序性细胞死亡受体-1(programmedcelldeathprotein1,PD-1)/程序性死亡受体配体-1(programmed death receptor-ligand 1,PD-L1)免疫检查点疗法临床响应率仍较低。C-X-C趋化因子配体12(C-X-C chemokine ligand 12,CXCL12)能够募集免疫抑制细胞,形成免疫抑制的肿瘤微环境,其受体C-X-C趋化因子受体4(C-X-C motif chemokine receptor 4,CXCR4)在胰腺癌等多种肿瘤中高表达,参与肿瘤的发生发展及侵袭转移。本研究通过双特异性anti-PD-L1&CXCR4纳米抗体(anti-PD-L1&CXCR4 bispecific nanobody,BsNb PX4)联合吉西他滨,能够协同增强人外周血单核细胞(human peripheral blood mononuclear cell,hPBMC)的抗肿瘤免疫效应。在吉西他滨预处理的hPBMC与肿瘤细胞共孵育体系中,加入双特异性anti-PD-L1&CXCR4纳米抗体,能够提高hPBMC杀伤肿瘤细胞的活性;流式细胞术分析证明,BsNb PX4与吉西他滨联用能够增加CD8^(+)/CD4^(+)T细胞的比例;体内实验表明,联合用药组的胰腺癌荷瘤NOD/SCID小鼠肿瘤组织中有更多CD8^(+)T细胞浸润,并且抑瘤效果优于单药组,为胰腺癌的免疫治疗提供了新的潜在治疗方式。人外周血单核细胞分离实验获得上海交通大学地方伦理委员会批准,动物福利和实验过程获得上海交通大学动物伦理委员会批准(批准号:A2024246)。Pancreatic cancer is a kind of highly malignant tumor with a low survival rate and poor prognosis.The effectiveness of gemcitabine as a first-line chemotherapy drug is limited;however,it can activate dendritic cells and improve antigen presentation which increase the sensitivity of tumor cell to immunotherapy.Although immunotherapy has made some advancements in cancer treatment,the therapeutic benefit of programmed cell death receptor 1/programmed death receptor-ligand 1(PD-1/PD-L1)blockade therapy remains relatively low.The chemokine C-X-C chemokine ligand 12(CXCL12)contributes to an immunosuppressive tumor microenvironment by recruiting immunosuppressive cells.The receptor C-X-C motif chemokine receptor 4(CXCR4),highly expressed in various tumors including pancreatic cancer,plays a crucial role in tumor development and progression.In this study,the anti-tumor immune response of human peripheral blood mononuclear cell(hPBMC)was enhanced using the combination of BsNb PX4(anti-PD-L1&CXCR4 bispecific nanobody)and gemcitabine.In a co-culture system of gemcitabine-pretreated hPBMCs with tumor cells,the BsNb PX4 synergized gemcitabine to improve the cytotoxic activity of hPBMCs against tumor cells.Flow cytometry analysis confirmed increased ratio of CD8^(+)to CD4^(+)T cells in combination treatment.In NOD/SCID mice bearing pancreatic cancer,the combination treatment exhibited more infiltration of CD8^(+)T cells into tumor tissues,contributing to an effective anti-tumor response.This study presents potential new therapies for the treatment of pancreatic cancer.Ethical approval was obtained for collection of hPBMC samples from the Local Ethics Committee of Shanghai Jiao Tong University.All animal experiments were approved by the Animal Ethic Committee of Shanghai Jiao Tong University(authorizing number:A2024246).

关 键 词：胰腺癌 程序性死亡受体配体-1 C-X-C趋化因子受体4 双特异性纳米抗体 化疗药物 外周血单核 

分 类 号：R966[医药卫生—药理学]