Interferon-γ-induced PD-L1 surface expression on human oral squamous carcinoma via PKD2 signal pathway
Interferon-γ-induced PD-L1 surface expression on human oral squamous carcinoma via PKD2 signal pathway
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DOI：
10.1016/j.imbio.2011.10.016
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发表时间：
2012-04-01
期刊：
影响因子：
2.8
通讯作者：
Zhang, Ping
中科院分区：
文献类型：
--
作者：
Chen, Jiao;Feng, Yun;Zhang, Ping
位于肿瘤微环境中的许多细胞的功能是保护或促进肿瘤细胞逃避免疫破坏的能力。先前的研究表明，程序性死亡配体-1(PD-L1)是137超家族的一种配体，表达在一系列人类肿瘤上，可以抑制抗肿瘤免疫反应。干扰素-γ是肿瘤微环境中炎性细胞产生和分泌的一种细胞因子，是肿瘤细胞表达PD-L1的主要刺激因子。弄清干扰素-γ诱导肿瘤细胞表达PD-L1的机制，有利于寻找抑制PD-L1功能、提高肿瘤细胞反应性免疫应答的途径。在此，我们发现蛋白激酶D异构体2(PKD2)是干扰素-γ诱导人口腔鳞癌细胞PD-L1表达的重要调节因子。干扰素-γ以时间和剂量依赖方式诱导人口腔鳞癌Tca8113细胞PD-L1和PKD2的表达。用shRNA/siRNA干扰或用干扰素-γ诱导的PKD化学抑制剂阻断PKD2后，PD-L1的表达显著降低。肿瘤细胞通过PD-1/PD-L1途径诱导的CD8(+)T细胞的凋亡率明显减少，肿瘤抗原特异性T细胞的体内抗肿瘤作用增强。综上所述，这些数据结合我们之前的结果，表明PKD2是肿瘤生物治疗的重要候选靶点。抑制PKD2的激活不仅可以抑制PD-L1的表达，促进抗肿瘤作用，还可以减少化疗中的耐药性。(C)2011年爱思唯尔股份有限公司。版权所有。
Many cells located in the tumor microenvironment function to protect or promote the ability of tumor cells to escape immune destruction. Previous studies have shown that programmed death ligand-1 (PD-L1), a ligand of the 137 superfamily, is expressed on a series of human tumors and can inhibit anti-tumor immune responses. Interferon-gamma (IFN-gamma), a cytokine produced and secreted by inflammatory cells in the tumor microenvironment, is a main stimulator of PD-L1 expression in tumor cells. Making clear the mechanism of IFN-gamma induced the expression of PD-L1 on tumor cells that is benefit to find a way to inhibit the function of PD-L1 and improve cancer cell-reactive immune responses. Herein, we have identified protein kinase D isoform 2 (PKD2) as an important regulator of PD-L1 expression on human oral squamous carcinoma cells induced by IFN-gamma. IFN-gamma induced the expression of PD-L1 and PKD2 in human oral squamous carcinoma Tca8113 in both time and dose dependent manner. The expression of PD-L1 was decreased significantly after PKD2 knockdown with shRNA/siRNA interference or PKD chemical inhibitor following induction with IFN-gamma. The apoptosis of CD8(+) T cell which is induced by tumor cells via PD-1/PD-L1 pathway was significantly decreased, as a result, the anti-tumor effects of tumor antigen specific T cell were increased in vivo. Together, these data combined with our previous results, indicate PKD2 as an important target candidate for tumor biotherapy. Inhibition of PKD2 activation not only inhibits PD-L1 expression and promotes an anti-tumor effect, but also decreases drug resistance in chemotherapy. (C) 2011 Elsevier GmbH. All rights reserved.