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    The effect of hypoxia on PD-L1 expression in bladder cancer

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    Authors
    Smith, Vicky
    Mukherjee, Debayan
    Lunj, Sapna
    Choudhury, Ananya
    Hoskin, Peter J
    West, Catharine M L
    Illidge, Timothy M
    Affiliation
    Division of Cancer Sciences, University of Manchester, M20 4BX, Manchester, UK
    Issue Date
    2021
    
    Metadata
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    Abstract
    Introduction: Recent data has demonstrated that hypoxia drives an immunosuppressive tumour microenvironment (TME) via various mechanisms including hypoxia inducible factor (HIF)-dependent upregulation of programmed death ligand 1 (PD-L1). Both hypoxia and an immunosuppressive TME are targetable independent negative prognostic factors for bladder cancer. Therefore we sought to investigate whether hypoxia is associated with upregulation of PD-L1 in the disease. Materials and methods: Three human muscle-invasive bladder cancer cell lines (T24, J82, UMUC3) were cultured in normoxia (20% oxygen) or hypoxia (1 and 0.1% oxygen) for 24 h. Differences in PD-L1 expression were measured using Western blotting, quantitative polymerase chain reaction (qPCR) and flow cytometry (≥3 independent experiments). Statistical tests performed were unpaired t tests and ANOVA. For in silico work an hypoxia signature was used to apply hypoxia scores to muscle-invasive bladder cancers from a clinical trial (BCON; n = 142) and TCGA (n = 404). Analyses were carried out using R and RStudio and statistical tests performed were linear models and one-way ANOVA. Results: When T24 cells were seeded at < 70% confluence, there was decreased PD-L1 protein (p = 0.009) and mRNA (p < 0.001) expression after culture in 0.1% oxygen. PD-L1 protein expression decreased in both 0.1% oxygen and 1% oxygen in a panel of muscle-invasive bladder cancer cells: T24 (p = 0.009 and 0.001), J82 (p = 0.008 and 0.013) and UMUC3 (p = 0.003 and 0.289). Increasing seeding density decreased PD-L1 protein (p < 0.001) and mRNA (p = 0.001) expression in T24 cells grown in both 20 and 1% oxygen. Only when cells were 100% confluent, were PD-L1 protein and mRNA levels higher in 1% versus 20% oxygen (p = 0.056 and p = 0.037). In silico analyses showed a positive correlation between hypoxia signature scores and PD-L1 expression in both BCON (p = 0.003) and TCGA (p < 0.001) cohorts, and between hypoxia and IFNγ signature scores (p < 0.001 for both). Conclusion: Tumour hypoxia correlates with increased PD-L1 expression in patient derived bladder cancer tumours. In vitro PD-L1 expression was affected by cell density and decreased PD-L1 expression was observed after culture in hypoxia in muscle-invasive bladder cancer cell lines. As cell density has such an important effect on PD-L1 expression, it should be considered when investigating PD-L1 expression in vitro.
    Citation
    Smith V, Mukherjee D, Lunj S, Choudhury A, Hoskin P, West C, et al. The effect of hypoxia on PD-L1 expression in bladder cancer Vol. 21, BMC Cancer. Springer Science and Business Media LLC; 2021.
    Journal
    BMC Cancer
    URI
    http://hdl.handle.net/10541/624938
    DOI
    10.1186/s12885-021-09009-7
    PubMed ID
    34819027
    Type
    Article
    ae974a485f413a2113503eed53cd6c53
    10.1186/s12885-021-09009-7
    Scopus Count
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