Cross-talk between TNF-α and IFN-γ signaling in induction of B7-H1 expression in hepatocellular carcinoma cells
Cross-talk between TNF-α and IFN-γ signaling in induction of B7-H1 expression in hepatocellular carcinoma cells
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TNF-α 和 IFN-γ 信号之间的串扰诱导肝细胞癌细胞中 B7-H1 表达
DOI：
10.1007/s00262-017-2086-8
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发表时间：
2018-02-01
影响因子：
5.8
通讯作者：
Shi, Yongyu
中科院分区：
文献类型：
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作者：
Li, Na;Wang, Jianing;Shi, Yongyu
B7-H1/PD-1检查点阻断免疫治疗的临床益处表明，了解癌细胞中B7-H1表达的调控机制非常重要。作为对内源性抗肿瘤免疫的适应性反应，B7-H1在HCC细胞中表达上调。B7-H1的表达主要由HCC中肿瘤浸润性T细胞释放的IFN-γ诱导。此外，HCC是炎症相关癌症的原型，TNF-α是HCC炎症微环境的重要组成部分。本研究探讨TNF-α是否能促进IFN-γ诱导的肝癌细胞B7-H1的表达。我们发现JAK/STAT 1/IRF 1是IFN-γ诱导人肝癌细胞系B7-H1表达的主要途径。TNF-α和IFN-γ协同诱导肝癌细胞B7-H1的表达。TNF-α通过上调IFN-γ受体的表达增强IFN-γ信号通路，是其协同作用的机制。此外，在小鼠HCC细胞中，TNF-α和IFN-γ协同诱导的B7-H1表达促进了体内肿瘤生长。提示TNF-α可增强IFN-γ诱导的B7-H1介导的肝癌细胞获得性免疫抵抗。
Clinical benefit from immunotherapy of B7-H1/PD-1 checkpoint blockade indicates that it is important to understand the regulatory mechanism of B7-H1 expression in cancer cells. As an adaptive response to the endogenous antitumor immunity, B7-H1 expression is up-regulated in HCC cells. B7-H1 expression is induced mainly by IFN-γ released from tumor-infiltrating T cells in HCC. In addition, HCC is a prototype of inflammation-related cancer and TNF-α is a critical component of inflammatory microenvironment of HCC. In the present study, we asked whether TNF-α can promote the expression of B7-H1 induced by IFN-γ in HCC cells. We found that JAK/STAT1/IRF1 was the primary pathway responsible for induction of B7-H1 expression by IFN-γ in human HCC cell lines. TNF-α and IFN-γ synergistically induced the expression of B7-H1 in the HCC cells. Moreover, the mechanism of the synergy was that TNF-α enhanced IFN-γ signaling by upregulating the expression of IFN-γ receptors. Furthermore, B7-H1 expression induced synergistically by TNF-α and IFN-γ in murine HCC cells facilitated tumor growth in vivo. Our findings suggest that TNF-α may enhance the adaptive immune resistance mediated by IFN-γ-induced B7-H1 in HCC cells.