1. Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells
- Author
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Paul J. Grippo, Daniel R. Principe, Mario A. Shields, Krishan Kumar, Rosa F. Hwang, Katharine Collier, Hidayatullah G. Munshi, Sammy Grimaldo, Thao Pham, Meng Shang, Raul Urrutia, Kazumi Ebine, David J. Bentrem, and Brian DeCant
- Subjects
0301 basic medicine ,BRD4 ,Stromal cell ,lcsh:Medicine ,Cell Cycle Proteins ,Article ,B7-H1 Antigen ,03 medical and health sciences ,Interferon ,Cell Line, Tumor ,medicine ,Humans ,lcsh:Science ,Regulation of gene expression ,Gene knockdown ,Multidisciplinary ,Chemistry ,lcsh:R ,Pancreatic Stellate Cells ,Nuclear Proteins ,Bromodomain ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,030104 developmental biology ,IRF1 ,Hepatic stellate cell ,Cancer research ,lcsh:Q ,Carcinoma, Pancreatic Ductal ,Interferon Regulatory Factor-1 ,Transcription Factors ,medicine.drug - Abstract
The fibrotic reaction is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of fibrosis in vivo. While there is increasing interest in the regulation of PD-L1 expression in cancer and immune cells, the expression and regulation of PD-L1 in other stromal cells, such as PSCs, has not been fully evaluated. Here we show that PSCs in vitro express higher PD-L1 mRNA and protein levels compared to the levels present in PDAC cells. We show that inhibitors targeting bromodomain and extra-terminal (BET) proteins and BRD4 knockdown decrease interferon-γ (IFN-γ)-induced PD-L1 expression in PSCs. We also show that c-MYC, one of the well-established targets of BET inhibitors, does not mediate IFN-γ-regulated PD-L1 expression in PSCs. Instead we show that interferon regulatory factor 1 (IRF1) mediates IFN-γ-induced PD-L1 expression in PSCs. Finally, while we show that BET inhibitors do not regulate IFN-γ-induced IRF1 expression in PSCs, BET inhibitors decrease binding of IRF1 and BRD4 to the PD-L1 promoter. Together, these results demonstrate the interplay between IRF1 and BRD4 in the regulation of PD-L1 in PSCs.
- Published
- 2018