替莫唑胺联合 PD-1 抗体治疗小鼠原位脑胶质瘤模型。

Temozolomide combined with PD-1 Antibody therapy for mouse orthotopic glioma model.

机构信息

Department of Radiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China.

Department of Radiology, Shanghai East Hospital, Tongji University, Shanghai, 200123, China.

出版信息

Biochem Biophys Res Commun. 2018 Jul 2;501(4):871-876. doi: 10.1016/j.bbrc.2018.05.064. Epub 2018 May 18.

DOI:10.1016/j.bbrc.2018.05.064

PMID:29758196

Abstract

PURPOSE

Temozolomide (TMZ) is the most frequent adjuvant chemotherapy drug in gliomas. PDL1 expresses on various tumors, including gliomas, and anti-PD-1 antibodies have been approved for treating some tumors by FDA. This study was to evaluate the therapeutical potential of combined TMZ with anti-PD-1 antibody therapy for mouse orthotopic glioma model.

METHODS

We performed C57BL/6 mouse orthotopic glioma model by stereotactic intracranial implantation of glioma cell line GL261, mice were randomly divided into four groups: (1) control group; (2) TMZ group; (3) anti-PD-1 antibody group; (4) TMZ combined with anti-PD-1 antibody group. Then the volume or size of tumor was assessed by 7.0 T MRI and immunohistochemistry, and the number of CD4 and CD8 infiltrating cells in brain tumor and spleen was evaluated by immunohistochemistry. Western blot was used to evaluate the expression of PDL1. Furthermore, Overall survival of each group mice was also evaluated.

RESULTS

Overall survival was significantly improved in combined group compared to other groups (χ2 = 32.043, p < 0.01). The volume or size of tumor was significantly decreased in combined group compared with other groups (F = 42.771, P < 0.01). And the number of CD4 and CD8 infiltrating cells in brain tumor was also obviously increased in combined group (CD4 F = 45.67, P < 0.01; CD8 F = 53.75, P < 0.01).

CONCLUSION

Anti-PD1 antibody combined with TMZ therapy for orthotopic mouse glioma model could significantly improve the survival time of tumor-bear mice. Thus, this study provides the effective preclinical evidence for support clinical chemotherapy combined with immunotherapy for glioma patients.

摘要

目的

替莫唑胺（TMZ）是神经胶质瘤中最常用的辅助化疗药物。PD-L1 在各种肿瘤上表达，包括神经胶质瘤，并且抗 PD-1 抗体已被 FDA 批准用于治疗一些肿瘤。本研究旨在评估 TMZ 联合抗 PD-1 抗体治疗对小鼠原位神经胶质瘤模型的治疗潜力。

方法

我们通过立体定向颅内植入神经胶质瘤细胞系 GL261 建立 C57BL/6 小鼠原位神经胶质瘤模型，将小鼠随机分为四组：（1）对照组；（2）TMZ 组；（3）抗 PD-1 抗体组；（4）TMZ 联合抗 PD-1 抗体组。然后通过 7.0T MRI 和免疫组织化学评估肿瘤的体积或大小，通过免疫组织化学评估脑肿瘤和脾脏中浸润的 CD4 和 CD8 细胞数量。使用 Western blot 评估 PDL1 的表达。此外，还评估了每组小鼠的总生存率。

结果

与其他组相比，联合组的总生存率显著提高（χ2=32.043，p<0.01）。与其他组相比，联合组的肿瘤体积或大小显著减小（F=42.771，P<0.01）。并且联合组脑肿瘤中浸润的 CD4 和 CD8 细胞数量也明显增加（CD4 F=45.67，P<0.01；CD8 F=53.75，P<0.01）。