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

Kazumi Ebine; Krishan Kumar; Thao N. Pham; Mario Anthonio Shields; Katharine A. Collier; Meng Shang; Brian T. DeCant; Raul Urrutia; Rosa F. Hwang; Sam Grimaldo; Daniel R. Principe; Paul J. Grippo; David Jason Bentrem; Hidayatullah G Munshi

doi:10.1038/s41598-018-31658-1

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

Kazumi Ebine, Krishan Kumar^*, Thao N. Pham, Mario Anthonio Shields, Katharine A. Collier, Meng Shang, Brian T. DeCant, Raul Urrutia, Rosa F. Hwang, Sam Grimaldo, Daniel R. Principe, Paul J. Grippo, David Jason Bentrem, Hidayatullah G Munshi

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

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.

Original language	English (US)
Article number	13225
Journal	Scientific reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-31658-1
State	Published - Dec 1 2018

Funding

We thank David Tuveson (Cold Spring Harbor Laboratories, Cold Spring Harbor, New York, US) for providing KPC1199 and KPC1245 mouse cell lines. This work was supported by grants R01CA186885 (to H.G. Munshi) and R21CA220625 (to K. Kumar) from the NCI, and a Merit award I01BX002922 (to H.G. Munshi) from the Department of Veterans Affairs.

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Ebine, K., Kumar, K., Pham, T. N., Shields, M. A., Collier, K. A., Shang, M., DeCant, B. T., Urrutia, R., Hwang, R. F., Grimaldo, S., Principe, D. R., Grippo, P. J., Bentrem, D. J., & Munshi, H. G. (2018). Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells. Scientific reports, 8(1), Article 13225. https://doi.org/10.1038/s41598-018-31658-1

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

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.",

author = "Kazumi Ebine and Krishan Kumar and Pham, {Thao N.} and Shields, {Mario Anthonio} and Collier, {Katharine A.} and Meng Shang and DeCant, {Brian T.} and Raul Urrutia and Hwang, {Rosa F.} and Sam Grimaldo and Principe, {Daniel R.} and Grippo, {Paul J.} and Bentrem, {David Jason} and Munshi, {Hidayatullah G}",

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Ebine, K, Kumar, K, Pham, TN, Shields, MA, Collier, KA, Shang, M, DeCant, BT, Urrutia, R, Hwang, RF, Grimaldo, S, Principe, DR, Grippo, PJ, Bentrem, DJ & Munshi, HG 2018, 'Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells', Scientific reports, vol. 8, no. 1, 13225. https://doi.org/10.1038/s41598-018-31658-1

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T1 - Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells

AU - Ebine, Kazumi

AU - Kumar, Krishan

AU - Pham, Thao N.

AU - Shields, Mario Anthonio

AU - Collier, Katharine A.

AU - Shang, Meng

AU - DeCant, Brian T.

AU - Urrutia, Raul

AU - Hwang, Rosa F.

AU - Grimaldo, Sam

AU - Principe, Daniel R.

AU - Grippo, Paul J.

AU - Bentrem, David Jason

AU - Munshi, Hidayatullah G

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

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

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