上海交通大学学报（医学版）

上海交通大学学报（医学版） ›› 2020, Vol. 40 ›› Issue (1): 37-.doi: 10.3969/j.issn.1674-8115.2020.01.006

• 论著·基础研究 • 上一篇    下一篇

人源化免疫肺癌小鼠模型的建立及其在程序性死亡受体1抑制剂疗效评估中的作用

周 箴1，徐云华1，张菲菲2，赵 艺1，郭 林2，付国龙2，沈盛萍1，冷雪娇1   

  1. 1. 上海市胸科医院，上海交通大学附属胸科医院，上海肺部肿瘤临床医学中心，上海 200030；2. 上海立迪生物技术股份有限公司，上海 201203
  • 出版日期:2020-01-28 发布日期:2020-03-05
  • 通讯作者: 周 箴（1965—），女，主任医师，博士；电子信箱：Jenniferzhou1116@163.com。
  • 作者简介:周 箴（1965—），女，主任医师，博士；电子信箱：Jenniferzhou1116@163.com。
  • 基金资助:
    上海市科学技术委员会科研计划项目（16140902800）。

Establishment of a lung cancer momodel with humanized immunity and its role in efficacy evaluation of programmed death-1 inhibitors

ZHOU Zhen, XU Yun-hua, ZHANG Fei-fei, ZHAO Yi, GUO Lin, FU Guo-long, SHEN Sheng-ping, LENG Xue-jiao   

  1. 1. Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China; 2. Shanghai Lide Biotechnology Co. Ltd., Shanghai 201203, China
  • Online:2020-01-28 Published:2020-03-05
  • Supported by:
    Scientific Research Program of Science and Technology Commission of Shanghai Municipality (16140902800).

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摘要： 目的·建立表达程序性死亡配体1（programmed death-ligand 1，PD-L1）的人源化免疫肺癌动物模型，并研究该模型在评估程序性死亡受体1（programmed death-1，PD-1）抑制剂疗效中的作用。方法·取晚期非小细胞肺癌患者新鲜的活检组织样本，或恶性胸腔积液中的肿瘤细胞，接种至CB17-SCID小鼠（重症联合免疫缺陷小鼠）皮下，建立患者来源异种移植物模型（patient-derived xenograft model，PDX模型），通过免疫组织化学法检测PDX模型肿瘤PD-L1的表达情况。将成熟的人外周血单个核细胞与PDX模型肿瘤细胞混合后接种NCG小鼠（高度免疫缺陷小鼠），建立人源化免疫的肺癌PDX模型，并在该模型上验证PD-1抑制剂的疗效。结果·在16个临床来源样本建立的PDX模型中，有2个PD-L1表达为强阳性，4个表达为阳性，其余均为阴性。在PD-L1强阳性的人源化免疫肺癌PDX模型中，PD-1抑制剂信迪利单抗在初次给药后21 d的肿瘤生长抑制率为82.6%；在PD-L1阴性的人源化免疫肺癌PDX模型中，PD-1抑制剂未显示出抗肿瘤活性。结论·成功建立了表达PD-L1的人源化免疫肺癌小鼠模型，且能在该模型上评估PD-1抑制剂的疗效。

关键词: 程序性死亡配体1, 程序性死亡受体1抑制剂, 人源化免疫, 患者来源异种移植物模型, 肺癌

Abstract:

Objective · To establish a lung cancer momodel with humanized peripheral blood mononuclear cells (PBMC) expressing programmed death-ligand 1 (PD-L1), and study the role of the model in evaluating the efficacy of programmed death-1 (PD-1) inhibitors. Methods · Fresh biopsy tissue samples or tumor cells in malignant pleural effusion the patients with advanced non-small cell lung cancer were inoculated subcutaneously in CB17-SCID mice to establish patient-derived xenograft (PDX) models. The of PD-L1 in PDX models was detectedimmunohistochemistry. The mature human PBMC and PDX model tumor cells were mixed and then inoculated into NCG mice to establish a PDX model of lung cancer with humanized immunity, on which the efficacy of PD-1 inhibitor was verified. Results · Among the PDX models established16 clinical samples, 2 were strongly positive for PD-L1, 4 were positive, and the rest were negative. In the PDX model with strongly positive PD-L1, the tumor growth inhibition rate of cindilimab, an inhibitor of PD-1, was 82.6%, 21 days after the initial administration; in the PDX model with negative PD-L1, the inhibitor of PD-1 showed no antitumor activity. Conclusion · A PD-L1-expressing lung cancer momodel with humanized immunity is successfully established and the efficacy of PD-1 inhibitor can be evaluated on the model.

Key words: programmed death-ligand 1 (PD-L1), programmed death-1 (PD-1) inhibitor, humanized immunity, patient-derived xenograft model (PDX model), lung cancer