Journal Article

Interferon regulatory factor 1 (IRF-1) and IRF-2 regulate PD-L1 expression in hepatocellular carcinoma (HCC) cells

Zheng Leting, Yan, Bing, Yihe, Yan, Geller, David A, Du, Qiang

2020

Overview

The objective response rate of immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) with anti PD-L1/PD-1 therapy is low. Discovering the signaling pathways regulating PD-L1 might help to improve ICB response rates. Here, we investigate transcription factors IRF-1 and IRF-2 signaling pathways regulating PD-L1 in HCC cells. In vivo studies show that IRF-1 and PD-L1 mRNA expression in human HCC tumors are significantly repressed compared with noncancerous background liver. IRF-1, IRF-2, and PD-L1 mRNA expression correlated positively in HCC tumors. Increased IRF-1 mRNA expression was observed in patients with well-differentiated or early stage HCC tumors. In vitro studies show that IFN-γ induces PD-L1 mRNA and protein expression through upregulation of IRF-1 in mouse and human HCC cells. IRF-1, IRF-2, and PD-L1 mRNA expression is upregulated in murine HCC by co-culture with effector T cells from spleen cells incubated with anti-CD3/CD28 antibodies. IRF-2 over-expression down-regulates IFN-γ induced PD-L1 promoter activity and protein levels in a dose-dependent manner. We identify two IRF-1 response elements (IRE1/IRE2) in the upstream 5′-flanking region of the CD274 (PD-L1) gene promoter. Site-directed mutagenesis shows both IRE1 and IRE2 are functional in transfection promoter assays. IRF-1 traditionally functions as tumor suppressor gene. However, these novel findings show a complex role for IRF-1 which upregulates PD-L1 in the inflammatory tumor microenvironment. IRF-1 antagonizes IRF-2 for binding to the IRE promoter element in PD-L1 which gives new insight to the regulation of PD-L1/PD-1 pathways in HCC ICB therapy.

• Publisher: Springer Nature B.V
• Subject: CD28 antigen / CD3 antigen / Cell culture / Effector cells / Gene expression / Hepatocellular carcinoma / Immune checkpoint / Immune checkpoint inhibitors / Inflammation / Interferon regulatory factor / Interferon regulatory factor 1 / Liver cancer / Lymphocytes T / Overexpression / PD-1 protein / PD-L1 protein / Regulatory sequences / Signal transduction / Site-directed mutagenesis / Spleen / Transcription factors / Transfection / Tumor microenvironment / Tumor suppressor genes / Tumors / γ-Interferon