2. Academic Validation
  3. Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells

Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells

  • Sci Rep. 2018 Sep 5;8(1):13225. doi: 10.1038/s41598-018-31658-1.
Kazumi Ebine 1 2,  Krishan Kumar 3 4,  Thao N Pham 1,  Mario A Shields 5,  Katharine A Collier 1,  Meng Shang 1 2,  Brian T DeCant 1,  Raul Urrutia 6,  Rosa F Hwang 7,  Sam Grimaldo 8,  Daniel R Principe 8,  Paul J Grippo 8,  David J Bentrem 9 2 10,  Hidayatullah G Munshi 11 12 13
Affiliations

Affiliations

  • 1 Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 2 Jesse Brown VA Medical Center, Chicago, IL, USA.
  • 3 Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. [email protected].
  • 4 The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA. [email protected].
  • 5 Cold Spring Harbor Laboratory, Cold Spring Harbor, Cold Spring, NY, USA.
  • 6 Laboratory of Epigenetics and Chromatin Dynamics, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Epigenomics Translational Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
  • 7 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8 Department of Medicine, University of Illinois, Chicago, IL, USA.
  • 9 Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 10 The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA.
  • 11 Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. [email protected].
  • 12 Jesse Brown VA Medical Center, Chicago, IL, USA. [email protected].
  • 13 The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA. [email protected].
PMID: 30185888 DOI: 10.1038/s41598-018-31658-1
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.

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