RT Journal Article
SR Electronic
T1 Hypoxia induces transcriptional and translational downregulation of the type I interferon (IFN) pathway in multiple cancer cell types
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 715151
DO 10.1101/715151
A1 Ana Miar
A1 Esther Arnaiz
A1 Esther Bridges
A1 Shaunna Beedie
A1 Adam P Cribbs
A1 Damien J. Downes
A1 Robert Beagrie
A1 Jan Rehwinkel
A1 Adrian L. Harris
YR 2019
UL http://biorxiv.org/content/early/2019/07/25/715151.abstract
AB Hypoxia is a common phenomenon in solid tumours and is considered a hallmark of cancer. Increasing evidence shows that hypoxia promotes local immune suppression. Type I IFN is involved in supporting cytotoxic T lymphocytes by stimulating the maturation of dendritic cells (DCs) and enhancing their capacity to process and present antigens. However, there is little information about the relationship between hypoxia and the type I interferon (IFN) pathway, which comprises the sensing of double-stranded RNA and DNA (dsRNA/dsDNA), followed by IFNα/β secretion and transcription activation of IFN-stimulated genes (ISGs). The aims of this study were to determine both the effect and mechanisms of hypoxia on the I IFN pathway in breast cancer.There was a downregulation of the type I IFN pathway expression at mRNA and protein level in cancer cell lines under hypoxia in vitro and in vivo in xenografts. This pathway was suppressed at each level of signalling, from the dsRNA sensors (RIG-I, MDA5), the adaptor (MAVS), transcription factors (IRF3, IRF7, STAT1) and several ISGs (RIG-I, IRF7, STAT1, ADAR-p150). There was also lower IFN secretion under hypoxic conditions. HIF1 and HIF2 regulation of gene expression did not explain most of the effects. However, ATAC-Seq data revealed that in hypoxia peaks with STAT1 and IRF3 motifs had decreased accessibility.Thus hypoxia leads to an overall 50% downregulation of the type I IFN pathway due to repressed transcription and lower chromatin accessibility in a HIF1/2α-independent manner, which could contribute to immunosuppression in hypoxic tumours.