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Tytuł pozycji:

A secondary role for hypoxia and HIF1 in the regulation of (IFNγ-induced) PD-L1 expression in melanoma.

Tytuł:
A secondary role for hypoxia and HIF1 in the regulation of (IFNγ-induced) PD-L1 expression in melanoma.
Autorzy:
van Duijn A; Laboratory of Experimental Dermatology, Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Willemsen KJ; Laboratory of Experimental Dermatology, Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
van Uden NOP; Laboratory of Experimental Dermatology, Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Hoyng L; Department of Oncogenomics, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Erades S; Laboratory of Experimental Dermatology, Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Koster J; Department of Oncogenomics, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Luiten RM; Laboratory of Experimental Dermatology, Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Bakker WJ; Laboratory of Experimental Dermatology, Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. .
Źródło:
Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2022 Mar; Vol. 71 (3), pp. 529-540. Date of Electronic Publication: 2021 Jul 15.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Publication: Berlin : Springer Verlag
Original Publication: Berlin ; New York, NY : Springer International, c1982-
MeSH Terms:
Gene Expression Regulation, Neoplastic*
B7-H1 Antigen/*genetics
Hypoxia/*genetics
Hypoxia/*metabolism
Hypoxia-Inducible Factor 1/*metabolism
Interferon-gamma/*metabolism
Melanoma/*etiology
Melanoma/*metabolism
Animals ; B7-H1 Antigen/metabolism ; Cell Line, Tumor ; Humans ; Melanoma/pathology ; Melanoma/therapy ; Melanoma, Experimental ; Mice ; RNA, Small Interfering/genetics ; Signal Transduction ; Tumor Microenvironment/genetics ; Tumor Microenvironment/immunology ; Tumor-Associated Macrophages/immunology ; Tumor-Associated Macrophages/metabolism ; Tumor-Associated Macrophages/pathology
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Contributed Indexing:
Keywords: HIF1; Hypoxia; IFNγ; Immunotherapy; Melanoma; PD-L1
Substance Nomenclature:
0 (B7-H1 Antigen)
0 (CD274 protein, human)
0 (Hypoxia-Inducible Factor 1)
0 (RNA, Small Interfering)
82115-62-6 (Interferon-gamma)
Entry Date(s):
Date Created: 20210716 Date Completed: 20220228 Latest Revision: 20220228
Update Code:
20240105
PubMed Central ID:
PMC8854324
DOI:
10.1007/s00262-021-03007-1
PMID:
34268602
Czasopismo naukowe
Cancer cells are able to escape immune surveillance by upregulating programmed death ligand 1 (PD-L1). A key regulator of PD-L1 expression is transcriptional stimulation by the IFNγ/JAK/STAT pathway. Recent studies suggest that hypoxia can induce PD-L1 expression. As hypoxia presents a hallmark of solid tumor development, hypoxic control of PD-L1 expression may affect the efficacy of cancer immunotherapy. This study aims to explore the hypoxic regulation of PD-L1 expression in human melanoma, and its interaction with IFNγ-induced PD-L1 expression. Analysis of the cutaneous melanoma dataset from the cancer genome atlas revealed a significant correlation of the HIF1-signaling geneset signature with PD-L1 mRNA expression. However, this correlation is less pronounced than other key pathways known to control PD-L1 expression, including the IFNγ/JAK/STAT pathway. This secondary role of HIF1 in PD-L1 regulation was confirmed by analyzing single-cell RNA-sequencing data of 33 human melanoma tissues. Interestingly, PD-L1 expression in these melanoma tissues was primarily found in macrophages. However, also in these cells STAT1, and not HIF1, displayed the most pronounced correlation with PD-L1 expression. Moreover, we observed that hypoxia differentially affects PD-L1 expression in human melanoma cell lines. Knockdown of HIF1 expression indicated a minor role for HIF1 in regulating PD-L1 expression. A more pronounced influence of hypoxia was found on IFNγ-induced PD-L1 mRNA expression, which is controlled at a 952 bp PD-L1 promoter fragment. These findings, showing the influence of hypoxia on IFNγ-induced PD-L1 expression, are relevant for immunotherapy, as both IFNγ and hypoxia are frequently present in the tumor microenvironment.
(© 2021. The Author(s).)

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