M1 Macrophages Induce PD-L1 Expression in Hepatocellular Carcinoma Cells Through IL-1β Signaling
M1 Macrophages Induce PD-L1 Expression in Hepatocellular Carcinoma Cells Through IL-1β Signaling
复制标题
M1 巨噬细胞通过 IL-1 beta 信号传导诱导肝细胞癌细胞中 PD-L1 的表达
DOI：
10.3389/fimmu.2019.01643
复制
发表时间：
2019-07-16
影响因子：
7.3
通讯作者：
Shi, Yongyu
中科院分区：
文献类型：
--
作者：
Zong, Zhaoyun;Zou, Jiahuan;Shi, Yongyu
肝细胞癌（HCC）是炎症相关癌症的原型，含有M1样和M2样肿瘤相关巨噬细胞。M1巨噬细胞被认为是杀肿瘤的，但一些研究报告其促肿瘤作用。程序性细胞死亡配体（PD-L）1在肝癌细胞中表达，是介导肝癌免疫逃逸的关键检查点分子。肝癌细胞中PD-L1的表达是可诱导的。在本研究中，我们询问M1巨噬细胞是否诱导HCC细胞中PD-L1的表达。首先，通过生物信息学和免疫组织化学实验确定HCC组织中过滤中的M1巨噬细胞和PD-L1表达之间的关联。在GEO数据库中的90个HCC样本中，M1巨噬细胞的富集评分与PD-L1表达相关。此外，HCC细胞中CD 68 + HLA-DR + M1样巨噬细胞的浸润与PD-L1表达水平相关。此外，M1-条件培养基由来源于THP-1细胞、RAW 264.7细胞或鼠骨髓的M1巨噬细胞制备。这些上清液诱导HCC细胞中PD-L1的表达。此外，通过siRNA测定和受体阻断测定鉴定上清液中的炎性细胞因子IL-1 β以解释诱导型PD-L1表达。此外，通过CHIP分析揭示HCC细胞中的转录因子p65和IRF 1介导诱导型PD-L1表达。所有结果表明，M1巨噬细胞诱导HCC细胞中PD-L1的表达，支持M1巨噬细胞的促肿瘤作用。
Hepatocellular carcinoma (HCC) is a prototype of inflammation-related cancer, harboring M1-like and M2-like tumor-associated macrophages. M1 macrophages are thought to be tumoricidal, but some studies report its pro-tumor role. The programmed cell death-ligand (PD-L) 1 expressed in HCC cells is a critical checkpoint molecule to mediate immune escape of HCC. The PD-L1 expression in HCC cells is inducible. In the present study, we ask whether M1 macrophages induce the expression of PD-L1 in HCC cells. First, an association between M1 macrophage in filtration and PD-L1 expression in HCC tissues was determined by bioinformatics and immunohistochemistry experiments. The enrichment score of M1 macrophages was correlated to PD-L1 expression in 90 HCC samples from GEO database. Besides, infiltration of CD68 + HLA-DR + M1-like macrophages correlated with PD-L1 expression level in HCC cells. Moreover, M1-conditioned media was prepared from M1 macrophages derived from THP-1 cell, RAW264.7 cell or murine bone marrow. These supernatants induced expression of PD-L1 in HCC cells. Furthermore, inflammatory cytokine IL-1 beta in the supernatants was identi fi ed to account for the inducible PD-L1 expression by siRNA assay and receptor blockade assay. Additionally, transcription factor p65 and IRF1 in the HCC cells were revealed by CHIP assay to mediate the inducible PD-L1 expression. All the results demonstrate that M1 macrophages induced expression of PD-L1 in HCC cells, supporting the pro-tumor role of M1 macrophages.