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

Autor: 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. w.j.bakker@amsterdamumc.nl.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2022 Mar; Vol. 71 (3), pp. 529-540. Date of Electronic Publication: 2021 Jul 15.
DOI: 10.1007/s00262-021-03007-1
Abstrakt: 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).)
Databáze: MEDLINE
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