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A key regulator of PD-L1 expression is transcriptional stimulation by the IFN\u03b3\/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 IFN\u03b3-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 <jats:italic>PD-L1<\/jats:italic> mRNA expression. However, this correlation is less pronounced than other key pathways known to control PD-L1 expression, including the IFN\u03b3\/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 <jats:italic>PD-L1<\/jats:italic> 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 IFN\u03b3-induced <jats:italic>PD-L1<\/jats:italic> mRNA expression, which is controlled at a 952\u00a0bp <jats:italic>PD-L1<\/jats:italic> promoter fragment. These findings, showing the influence of hypoxia on IFN\u03b3-induced PD-L1 expression, are relevant for immunotherapy, as both IFN\u03b3 and hypoxia are frequently present in the tumor microenvironment.<\/jats:p>","DOI":"10.1007\/s00262-021-03007-1","type":"journal-article","created":{"date-parts":[[2021,7,15]],"date-time":"2021-07-15T20:02:21Z","timestamp":1626379341000},"page":"529-540","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["A secondary role for hypoxia and HIF1 in the regulation of (IFN\u03b3-induced) PD-L1 expression in melanoma"],"prefix":"10.1007","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4708-0952","authenticated-orcid":false,"given":"Anneloes","family":"van Duijn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin J.","family":"Willemsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9952-1065","authenticated-orcid":false,"given":"Nathalie O. 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