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Apatinib prevents natural killer cell dysfunction to enhance the efficacy of anti-PD-1 immunotherapy in hepatocellular carcinoma.
Cancer Gene Therapy ( IF 6.4 ) Pub Date : 2020-06-12 , DOI: 10.1038/s41417-020-0186-7
Yinli Yang 1, 2, 3 , Cong Wang 1, 2 , Haiyan Sun 1, 2 , Zhansheng Jiang 1, 2 , Yu Zhang 1, 2 , Zhanyu Pan 1, 2, 4
Affiliation  

Apatinib, a selective vascular endothelial growth factor receptor 2-tyrosine kinase inhibitor, has demonstrated activity against a wide range of solid tumors, including advanced hepatocellular carcinoma (HCC). Preclinical and preliminary clinical results have confirmed the synergistic antitumor effects of apatinib in combination with anti-programmed death-1 (PD-1) blockade. However, the immunologic mechanism of this combination therapy remains unclear. Here, using a syngeneic HCC mouse model, we demonstrated that treatment with apatinib resulted in attenuation of tumor growth and increased tumor vessel normalization. Moreover, our results indicated that natural killer cells, but not CD4+ or CD8+ T cells mediated the therapeutic efficacy of apatinib in HCC mouse models. As expected, the combined administration of apatinib and anti-PD-1 antibody into tumor-bearing mice generated potent immune responses resulting in a remarkable reduction of tumor growth. Furthermore, increased interferon-γ and decreased tumor necrosis factor-α and interleukin-6 levels were observed, suggesting the potential benefits of combination therapy with PD-1 blockade and apatinib in HCC.



中文翻译:

阿帕替尼可防止自然杀伤细胞功能障碍,以增强抗 PD-1 免疫疗法在肝细胞癌中的疗效。

阿帕替尼是一种选择性血管内皮生长因子受体 2-酪氨酸激酶抑制剂,已证明对多种实体瘤具有活性,包括晚期肝细胞癌 (HCC)。临床前和初步临床结果证实了阿帕替尼联合抗程序性死亡-1(PD-1)阻断剂的协同抗肿瘤作用。然而,这种联合疗法的免疫机制尚不清楚。在这里,我们使用同基因 HCC 小鼠模型证明了阿帕替尼治疗导致肿瘤生长减弱和肿瘤血管正常化增加。此外,我们的结果表明自然杀伤细胞,而不是 CD4 +或 CD8 +T 细胞介导了阿帕替尼在 HCC 小鼠模型中的治疗效果。正如预期的那样,将阿帕替尼和抗 PD-1 抗体联合给药到荷瘤小鼠体内产生了有效的免疫反应,从而显着减少了肿瘤的生长。此外,观察到干扰素-γ 增加和肿瘤坏死因子-α 和白细胞介素-6 水平降低,表明 PD-1 阻断剂和阿帕替尼联合治疗在 HCC 中的潜在益处。

更新日期:2020-06-12
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