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Cited by 162Cancer Immunotherapy and BiomarkersViral-associated cancers and disordersCytokine Signaling Pathways and Interactions

IFNγ induces PD-L1 overexpression by JAK2/STAT1/IRF-1 signaling in EBV-positive gastric carcinoma

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Moon, Ji Wook, Kong, Su-Kang, Kim, Byung Soo, Kim, Hyun Ji, Lim, Hyangsoon, Noh, Kyeonga, Kim, Younghye, Choi, Jung-Woo +2 more·2017·Scientific Reports
DOI 10.1038/s41598-017-18132-0PMC PMC5736657
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Abstract

Programmed death-ligand 1 (PD-L1) acts as an immune checkpoint inhibitor in various cancers. PD-L1 is known to be more frequently expressed in EBV (+) gastric cancer (GC). However, the mechanisms underlying the regulation of PD-L1 expression in EBV (+) GC remain unclear. We investigated the basal and inducible PD-L1 expressions in GC cells. PD-L1 expression was upregulated upon treatment with IFNγ in both EBV (−) and EBV (+) GC cells. Upon stimulation with the same concentration of IFNγ for 24 h, EBV (+) SNU-719 cells showed dramatically higher PD-L1 expression levels by activating JAK2/STAT1/IRF-1 signaling than those of EBV (−) AGS cells. PD-L1 promoter assays, chromatin immunoprecipitation, and electrophoretic mobility shift assays revealed that IFNγ-inducible PD-L1 overexpression is primarily mediated by the putative IRF-1α site of the PD-L1 promoter in EBV (+) SNU-719 cells. Moreover, EBNA1 knockdown reduced both constitutive and IFNγ-inducible PD-L1 promoter activity by decreasing the transcript and protein levels of JAK2 and subsequently STAT1/IRF-1/PD-L1 signaling. EBNA1 is suggested to be moderately enhance both constitutive and IFNγ-inducible PD-L1 expression in EBV (+) GC cells. Thus, the signaling proteins and EBNA1 that regulate PD-L1 expression are potential therapeutic targets in EBV (+) GC.

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  • Exposure to interferon gamma (IFNγ) rapidly induces PD-L1 expression both in cancer cell lines and in the tumor microenvironment.

    “Numerous studies have observed that exposure to interferon gamma (IFN γ ) rapidly induces PD-L1 expression both in cancer cell lines and in the tumor microenvironment [7-10].”

    From Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens (2021) · cites this paper as [9]

    The Results section reports that IFNγ increased PD-L1 expression in gastric cancer cell lines, with a marked increase by 24 hours. In tumor tissue, the paper observes high PD-L1 expression near infiltrating lymphocytes, but describes IFNγ-driven induction there as a hypothesis rather than a demonstrated response to exposure (Results and Discussion; page numbers unavailable). (LLM, conf=0.86)

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  • Among the eight genes whose perturbation shifted PD-L1 protein levels, five were positive regulators (PD-L1 downregulation upon perturbation) and three were negative regulators.

    “We identified five positive regulators (PD-L1 downregulation upon perturbation) and three negative regulators, a subset of which had been previously validated [9,11,13,16,17,29].”

    From Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens (2021) · cites this paper as [9]

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Research works printed but not linked: 34

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Authors
Moon, J. W., Kong, S.-K., Kim, B. S., Kim, H. J., Lim, H., Noh, K., Kim, Y., Choi, J.-W., Lee, J.-H., & Kim, Y.-S.
Affiliations
  • Korea University (KR)
  • Korea University Ansan Hospital (KR)
Corresponding author
  • Kim, Younghye
  • Kim, Young-Sik
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-12-19
Volume
7
Issue
1
Pages
17810-17810
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-18132-0
PMC
PMC5736657
OpenAlex
W2773629709
Cited by
162
References
37
Citations by year
2026: 17 · 2025: 28 · 2024: 22 · 2023: 18 · 2022: 24 · 2021: 20 · 2020: 16 · 2019: 11 · 2018: 5
FWCI
3.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Research Foundation
  • National Research Foundation of Korea (2016 R1A2B4012030)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
PD-L1, interferon-gamma, JAK2/STAT1 signaling, IRF1, EBNA1, immune checkpoint, AGS cells
MeSH terms
Herpesvirus 4, Human, Humans, Interferon-gamma, Proteins, Stomach Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Epstein-Barr Virus Infections, Cell Line, Tumor, STAT1 Transcription Factor, Interferon Regulatory Factor-1, Janus Kinase 2, B7-H1 Antigen

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