目的：探讨程序性死亡受体-1（PD-1）单抗联合顺铂或吉西他滨在KRAS基因突变非小细胞肺癌（NSCLC）A549 细胞移植瘤小鼠模型治疗中的作用。方法：构建免疫系统-肿瘤双人源化A549 细胞小鼠移植瘤模型，将60只小鼠按随机数字表法分成6组（10 只/组），分别为对照组（200 μL/kg PBS）、PD-1单抗组（20 mg/kg PD-1单抗）、顺铂组（3 mg/kg 顺铂）、PD-1单抗+顺铂组（20 mg/kg PD-1 单抗+3 mg/kg 顺铂）、吉西他滨组（30 mg/kg 吉西他滨）和PD-1 单抗+吉西他滨组（20 mg/kg PD-1 单抗+30 mg/kg吉西他滨）。TUNEL和DAPI双染色法检测移植瘤组织中细胞凋亡水平，测量移植瘤体积和质量并计算肿瘤生长抑制率，免疫组化法检测移植瘤微血管密度（MVD）。结果：成功构建免疫系统-肿瘤双人源化NSCLC A549细胞小鼠移植瘤模型，PD-1单抗+顺铂组移植瘤的细胞凋亡率、肿瘤生长抑制率均最高，移植瘤体积、质量和MVD 均最小，与其他5 组小鼠比较差异均有统计学意义（均P<0.05）。结论：顺铂与PD-1单抗具有协同活性，而吉西他滨拮抗PD-1单抗的治疗作用。提示PD-1单抗联合顺铂对KRAS突变NSCLC A549细胞移植瘤小鼠的疗效更好。

Objective: To investigate the therapeutic effect of programmed death-1 monoclonal antibody (PD-1 mAb) combined with cisplatin and gemcitabine in the treatment of transplanted tumor with KRAS gene mutant non-small cell lung cancer (NSCLC) A549 cells in mice.Methods: By constructing an immune system-tumor humanized mouse xenograft model with NSCLC A549 cells, 60 mice were randomly divided into 6 groups (10 mice/group), namely control group (200 μL/kg PBS), PD-1 mAb group (20 mg/kg PD-1 mAb), cisplatin group (3 mg/kg cisplatin), PD-1 mAb+cisplatin group (20 mg/kg PD-1 mAb+3 mg/kg cisplatin), gemcitabine group (30 mg/kg gemcitabine) and PD-1 mAb+gemcitabine group (20 mg/kg PD-1 mAb+30 mg/kg gemcitabine). TUNEL and DAPI double staining were used to detect the level of apoptosis in transplanted tumor tissues. The volume and mass of transplanted tumors were detected, and the growth inhibition rate of transplanted tumor was measured. The microvessel density (MVD) of transplanted tumor was determined by immunohistochemistry. Results: The humanized mouse xenograft model of NSCLC A549 cells was successfully constructed. Compared with the other five groups, the apoptosis rate and tumor growth inhibition rate in the PD-1 mAb+cisplatin group were the highest, and the tumor volume, mass, and MVD were the smallest (all P<0.05 ). Conclusion: Cisplatin has a synergistic activity with PD-1 mAb, while gemcitabine can antagonize the therapeutic effect of PD-1 mAb. It is suggested that PD-1 mAb combined with cisplatin chemotherapy is better for KRAS mutant NSCLC A549 cell transplanted tumor mice.

湖北省卫生健康委员会科研项目（No. WJ2019M095）