Blocking the PD-1/PD-L1 axis in dendritic cell-stimulated Cytokine-Induced Killer Cells with pembrolizumab enhances their therapeutic effects against hepatocellular carcinoma
Blocking the PD-1/PD-L1 axis in dendritic cell-stimulated Cytokine-Induced Killer Cells with pembrolizumab enhances their therapeutic effects against hepatocellular carcinoma
复制标题
用派姆单抗阻断树突状细胞刺激的细胞因子诱导的杀伤细胞中的 PD-1/PD-L1 轴可增强其对肝细胞癌的治疗效果
DOI：
10.7150/jca.26961
复制
发表时间：
2019-01-01
影响因子：
3.9
通讯作者：
Li, Aimin
中科院分区：
文献类型：
--
作者：
Zhang, Wan;Song, Zhenghui;Li, Aimin
癌症的免疫检查点疗法，如抗程序性细胞死亡1（PD-1）药物pembrolizumab，已经获得了相当大的关注。然而，在过继免疫治疗的背景下使用免疫检查点抑制剂的特征很差。我们研究了树突状细胞刺激的CIK（DC-CIK）细胞预处理与帕博利珠单抗对肝细胞癌（HCC）在体外细胞毒性试验和裸鼠移植瘤模型的治疗效果。我们使用延时成像来研究肿瘤杀伤。我们还使用癌症基因组图谱（TCGA）HCC队列（n=371例患者）基于淋巴细胞亚群特异性mRNA特征进行了生存分析。结果表明，PD-1抑制增加了DC-CIK细胞的抗肿瘤作用超过单独的DC-CIK细胞的抗肿瘤作用，导致重要的存活益处。延时成像显示，DC-CIK细胞在抗PD-1治疗后似乎比在对照条件下培养后更有效和更具攻击性。PD-1抑制剂还诱导了肿瘤的更有效的免疫细胞浸润。我们对TCGA HCC队列的分析证实，与肿瘤内高度CD 8 + T细胞浸润一致的基因特征与良好预后相关。这些结果表明，在输注前用PD-1抑制剂阻断DC-CIK细胞中的PD-1/PD-L1轴是一种有前景的抗HCC治疗策略。
Immune checkpoint therapies for cancer, like the anti-programmed cell death 1 (PD-1) agent pembrolizumab, have gained considerable attention. However, the use of immune checkpoint inhibitors in the context of adoptive immunotherapy is poorly characterized. We investigated the therapeutic efficacy of dendritic cell-stimulated CIK (DC-CIK) cells pretreated with pembrolizumab against hepatocellular carcinoma (HCC) in cytotoxicity assay in vitro and in a nude mouse xenograft model. We used time-lapse imaging to investigate tumor killing. We also performed a survival analysis based on lymphocyte subpopulation-specific mRNA signatures using The Cancer Genome Atlas (TCGA) HCC cohort (n=371 patients). The results indicated that PD-1 inhibition increased the anti-tumor effects of DC-CIK cells over those of DC-CIK cells alone, resulting in a survival benefit importantly. Time-lapse imaging revealed that DC-CIK cells appeared to be more effective and aggressive after anti-PD-1 treatment than after culture in control conditions. The PD-1 inhibitor also induced more effective immune cell infiltration of the tumor. Our analysis of the TCGA HCC cohort confirmed that a genetic signature consistent with a high degree of intratumoral CD8+ T cell infiltration is associated with good prognosis. These results suggest that blockade of the PD-1/PD-L1 axis in DC-CIK cells with a PD-1 inhibitor prior to infusion is a promising therapeutic strategy against HCC.