Department of Immunology, Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Shandong University, 44# Wenhua Xi Road, Jinan 250012, China.
Department of Parasitology, School of Basic Medical Science, Shandong University, Jinan, China.
Mol Immunol. 2018 Sep;101:203-209. doi: 10.1016/j.molimm.2018.07.006. Epub 2018 Jul 5.
The effectiveness of immunotherapy targeting the immune checkpoint PD-L1/PD-1 pathway highlights importance of elucidating the regulatory mechanisms of PD-L1 expression in cancer cells. Previous studies demonstrate that oncogene MYC up-regulates PD-L1 expression in lymphomas. In the present study, we investigated the regulatory role of MYC in the PD-L1 expression induced by IFN-γ in HCC cells. Unexpectedly, knockdown of MYC expression using siRNA assay increased the inducible expression of PD-L1 both at mRNA and protein levels. Mechanistically, the inhibition of MYC elevated expression of STAT1, a critical component of IFN-γ signaling pathway, leading to the elevation of PD-L1 expression in HCC cells exposed to IFN-γ. These results suggest that MYC may down-regulate PD-L1 expression in the context of HCC. This study implicates that a combination therapy targeting MYC function and PD-L1/PD-1 pathway might be effective for treatment of HCC.
免疫疗法靶向免疫检查点 PD-L1/PD-1 通路的疗效凸显了阐明癌细胞中 PD-L1 表达的调节机制的重要性。先前的研究表明，癌基因 MYC 上调淋巴瘤中 PD-L1 的表达。在本研究中，我们研究了 MYC 在 IFN-γ诱导的 HCC 细胞中 PD-L1 表达中的调节作用。出乎意料的是，siRNA 实验中 MYC 表达的敲低增加了 PD-L1 在 mRNA 和蛋白水平上的诱导表达。从机制上讲，MYC 的抑制作用提高了 IFN-γ信号通路的关键组成部分 STAT1 的表达，导致暴露于 IFN-γ的 HCC 细胞中 PD-L1 的表达升高。这些结果表明，MYC 可能在 HCC 的背景下下调 PD-L1 的表达。这项研究表明，针对 MYC 功能和 PD-L1/PD-1 通路的联合治疗可能对 HCC 的治疗有效。
