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- W4313373386 abstract "Abstract Novel therapies for the pediatric brain tumor medulloblastoma (MB) are hindered by limited knowledge of the roles played by host-derived cells at the local tumor site. Immune resistance in a murine model of MB (MM1) is associated with enhanced tumor expression of programmed death ligand-1 (PD-L1) in response to anti-tumor cytokine interferon-gamma (IFNγ) signaling. Disrupting this pathway via knockdown of cyclin dependent kinase 5 (CDK5), an essential transducer of the IFNγ signal, leads to an inflammatory tumor microenvironment (TME) and enhanced tumor rejection in vivo. In this study, we sought to detail the mechanism of CDK5-mediated PD-L1 regulation. In response to IFNγ, PD-L1 expression is thought to be regulated at the promoter level by competition between the transcriptional activator IRF1 and repressor IRF2. We hypothesized that CDK5-IFNγ signaling inhibits IRF2 activity, resulting in unleashed PD-L1 promoter activity. We assessed IRF1/IRF2-DNA interactions using chromatin immunoprecipitation (ChIP) and gene reporter assays, with complementary analysis of PD-L1 transcription and surface expression with IRF1/IRF2 depletion. ChIP-qPCR revealed a similar, IFNγ-induced enrichment of both IRF1 and IRF2 at the PD-L1 promoter. This is a surprising result, given the assumption that they compete for the same binding site and exert opposing effects. Additionally, inducible PD-L1 promoter activity was found to be decreased in tumors with IRF2 depletion. Together, these results suggest that IRF2 may be necessary for full activity of the PD-L1 promoter in MB. IRF1/IRF2 also bind to other cis-regulatory sites at genes that contribute to tumor immunogenicity, necessitating genome-wide characterization of their interactions." @default.
- W4313373386 created "2023-01-06" @default.
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- W4313373386 date "2020-05-01" @default.
- W4313373386 modified "2023-10-16" @default.
- W4313373386 title "Detailing the mechanism of CDK5-mediated PD-L1 regulation in Medulloblastoma" @default.
- W4313373386 doi "https://doi.org/10.4049/jimmunol.204.supp.165.38" @default.
- W4313373386 hasPublicationYear "2020" @default.
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