探讨PD-1抑制剂在不同小鼠肿瘤模型中的应答差异

白杰; 高志涛; 石龙; 底静; 李嵩; 李祥; 聂晶; 韩为东

doi:10.3969/j.issn.2095-5227.2019.04.013

探讨PD-1抑制剂在不同小鼠肿瘤模型中的应答差异

Differential PD-1 inhibitor efficacy among different mouse tumor models

摘要

摘要:
目的探讨不同肿瘤小鼠荷瘤模型对PD-1(programmed death-1)抑制剂应答的差异。
方法构建免疫健全小鼠荷瘤模型(B16黑色素瘤、CT26结肠癌、MC38结肠癌荷瘤模型)，B16黑色素瘤与CT26结肠癌肿瘤模型设置以下两组：PBS对照组，PD-1抑制剂治疗组；MC38结肠癌肿瘤模型设置以下四组：PBS对照组，PD-1抑制剂治疗组，PD-1抑制剂治疗高剂量组以及PD-1抑制剂延迟治疗组；记录各组小鼠肿瘤大小，绘制肿瘤生长曲线与小鼠生存曲线。采用小鼠CD8磁珠分选肿瘤浸润CD8⁺ T淋巴细胞分析其绝对数量差异，流式细胞术分析各组小鼠肿瘤T细胞亚群的比例差异，探究PD-1抑制剂抗瘤活性相关免疫细胞类型及其变化。
结果 CT26结肠癌小鼠荷瘤模型对PD-1抑制剂相对抵抗；B16黑色素瘤小鼠荷瘤模型对PD-1抑制剂应答不敏感；MC38结肠癌小鼠荷瘤模型对PD-1抑制剂的应答相对敏感并存在个体差异性，且与PD-1抑制剂治疗时间与剂量相关；PD-1抑制剂治疗后肿瘤浸润CD8⁺ T淋巴细胞绝对数量增加(P均＜0.05)，CD8⁺ Ki67⁺、CD8⁺ IFN-γ⁺、CD8⁺ Ki67⁺ IFN-γ⁺ T淋巴细胞比例均上升(P均＜0.05)。
结论 MC38结肠癌小鼠荷瘤模型为研究PD-1抑制剂抗瘤效应的适宜模型；PD-1抑制剂能够促进肿瘤浸润CD8⁺ T细胞的增殖与功能，增强抗肿瘤免疫反应。

Abstract:
Objective To explore the different responses to PD-1 (programmed death-1) inhibitor in different mouse tumor models.
Methods Mouse tumor models, including B16 melanoma, CT26 colon cancer, MC38 colon cancer, were established. B16 melanoma and CT26 colon cancer tumor models were divided into control group and PD-1 inhibitor treatment group, and MC38 colon cancer tumor model was divided into four groups, control group, PD-1 inhibitor treatment group, high dose PD-1 inhibitor treatment group and delayed PD-1 inhibitor treatment group. Tumor size data in each group was recorded, tumor growth and survival curve were drawn. The tumor infiltrating CD8⁺ T lymphocytes were sorted by CD8 beads and the quantitative differences were analyzed. The tumor infiltrating T lymphocyte subsets were measured by flow cytometry to explore the types of immune cells related to the anti-tumor activity of PD-1 inhibitor.
Results PD-1 inhibitor had no anti-tumor efficacy in CT26 colon tumor model, and minor anti-tumor efficacy in B16 melanoma tumor model; but significant anti-tumor efficacy in MC38 colon tumor model. The efficacy varied by treatment duration and dose of PD-1 inhibitor in MC38 colon tumor model. After PD-1 inhibitor treatment, the absolute number of tumor infiltrating CD8⁺ T lymphocytes increased, and the proportion of CD8⁺ Ki67⁺, CD8⁺ IFN-γ⁺, CD8⁺ Ki67⁺ IFN-γ⁺ tumor infiltrating T lymphocytes all increased (P < 0.05, respectively).
Conclusion MC38 colon tumor model is appropriate to study the anti-tumor efficacy of PD-1 inhibitor; PD-1 inhibitor can promote the proliferation and function of tumor infiltrating CD8⁺ T cells and enhance the anti-tumor immune response.

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