IFN-γ down-regulates the PD-1 expression and assist nivolumab in PD-1-blockade effect on CD8+T-lymphocytes in pancreatic cancer
IFN-γ down-regulates the PD-1 expression and assist nivolumab in PD-1-blockade effect on CD8+T-lymphocytes in pancreatic cancer
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IFN-gamma 下调 PD-1 表达并协助纳武单抗对胰腺癌 CD8 T 淋巴细胞发挥 PD-1 阻断作用
DOI：
10.1186/s12885-019-6145-8
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发表时间：
2019-11-06
期刊：
影响因子：
3.8
通讯作者：
Cao, Liping
中科院分区：
文献类型：
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作者：
Ding, Guoping;Shen, Tao;Cao, Liping
胰腺癌具有高度免疫抑制的肿瘤微环境和逃避免疫监测的特点。尽管程序性细胞死亡1受体（PD-1）阻断在免疫原性癌症中取得了一定的成功，但对PD-1抗体的反应在胰腺癌患者中并不有效或持续。方法首先检测胰腺癌患者和健康供者外周血CD8+ t淋巴细胞中PD-1的表达。在体外研究中，分离外周t淋巴细胞并给予纳武单抗和/或干扰素- γ处理，然后检测不同处理后的pd -1阻断效应、增殖、细胞因子分泌和细胞毒活性。在体内研究中，用诱导t淋巴细胞处理皮下胰腺癌细胞系小鼠，并测量肿瘤大小。结果胰腺导管腺癌患者外周血CD8+ T细胞中PD-1蛋白表达明显高于正常供者。在体外实验中，纳武单抗以浓度依赖性的方式降低CD8+ t淋巴细胞上PD-1的表达。ifn - γ在体外可直接下调PD-1的表达。此外，nivolumab和IFN-gamma联合治疗pd -1阻断的效果最大（1.73 +/- 0.78），而IFN-gamma沿治疗（18.63 +/- 0.82）和nivolumab沿治疗（13.65 +/- 1.22）。此外，nivolumab联合ifn - γ的作用最大程度地促进了t淋巴细胞的增殖功能、细胞因子分泌和细胞毒活性。最重要的是，纳武单抗联合ifn - γ诱导的t淋巴细胞对肿瘤生长的抑制效果最好。结论ifn - γ联合pd -1阻断剂可增强免疫功能，可能在胰腺癌过继转移治疗中发挥重要作用。
Background Pancreatic cancer is characterized by a highly immunosuppressive tumor microenvironment and evasion of immune surveillance. Although programmed cell death 1 receptor (PD-1) blockade has achieved certain success in immunogenic cancers, the responses to the PD-1 antibody are not effective or sustained in patients with pancreatic cancer. Methods Firstly, PD-1 expressions on peripheral CD8+ T-lymphocytes of patients with pancreatic cancer and healthy donors were measured. In in vitro study, peripheral T-lymphocytes were isolated and treated with nivolumab and/or interferon-gamma, and next, PD-1-blockade effects, proliferations, cytokine secretions and cytotoxic activities were tested after different treatments. In in vivo study, mice bearing subcutaneous pancreatic cancer cell lines were treated with induced T-lymphocytes and tumor sizes were measured. Results PD-1 protein expression is increased on peripheral CD8+ T cells in patients with pancreatic ductal adenocarcinoma compared with that in health donor. PD-1 expression on CD8+ T-lymphocytes was decreased by nivolumab in a concentration-dependent manner in vitro. IFN-gamma could directly down-regulate expression of PD-1 in vitro. Furthermore, the combination therapy of nivolumab and IFN-gamma resulted in greatest effect of PD-1-blockde (1.73 +/- 0.78), compared with IFN-gamma along (18.63 +/- 0.82) and nivolumab along (13.65 +/- 1.22). Moreover, the effects of nivolumab plus IFN-gamma largest promoted the T-lymphocytes function of proliferations, cytokine secretions and cytotoxic activities. Most importantly, T-lymphocytes induced by nivolumab plus IFN-gamma presented the best repression of tumor growth. Conclusions IFN-gamma plus a PD-1-blockading agent could enhance the immunologic function and might play a crucial role in effective adoptive transfer treatments of pancreatic cancer.