Hypoxia induces transcriptional and translational downregulation of the type I IFN pathway in multiple cancer cell types
Hypoxia is a common phenomenon in solid tumors and is strongly linked to hallmarks of cancer. Recent evidence has shown that hypoxia promotes local immune suppression. Type I IFN supports cytotoxic T lymphocytes by stimulating the maturation of dendritic cells and enhancing their capacity to process...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Association for Cancer Research
2020
|
| _version_ | 1826275975238778880 |
|---|---|
| author | Miar, A Arnaiz, E Bridges, E Beedie, S Cribbs, AP Downes, DJ Beagrie, RA Rehwinkel, J Harris, AL |
| author_facet | Miar, A Arnaiz, E Bridges, E Beedie, S Cribbs, AP Downes, DJ Beagrie, RA Rehwinkel, J Harris, AL |
| author_sort | Miar, A |
| collection | OXFORD |
| description | Hypoxia is a common phenomenon in solid tumors and is strongly linked to hallmarks of cancer. Recent evidence has shown that hypoxia promotes local immune suppression. Type I IFN supports cytotoxic T lymphocytes by stimulating the maturation of dendritic cells and enhancing their capacity to process and present antigens. However, little is known about the relationship between hypoxia and the type I IFN pathway, which comprises the sensing of double-stranded RNA and DNA (dsRNA/dsDNA) followed by IFNα/β secretion and transcriptional activation of IFN-stimulated genes (ISG). In this study, we determined the effects of hypoxia on the type I IFN pathway in breast cancer and the mechanisms involved. In cancer cell lines and xenograft models, mRNA and protein expressions of the type I IFN pathway were downregulated under hypoxic conditions. This pathway was suppressed at each level of signaling, from the dsRNA sensors RIG-I and MDA5, the adaptor MAVS, transcription factors IRF3, IRF7, and STAT1, and several ISG including RIG-I, IRF7, STAT1, and ADAR-p150. Importantly, IFN secretion was reduced under hypoxic conditions. HIF1α- and HIF2α-mediated regulation of gene expression did not explain most of the effects. However, ATAC-seq data revealed in hypoxia that peaks with STAT1 and IRF3 motifs had decreased accessibility. Collectively, these results indicate that hypoxia leads to an overall downregulation of the type I IFN pathway due to repressed transcription and lower chromatin accessibility in an HIF1/2α-independent manner, which could contribute to immunosuppression in hypoxic tumors.
|
| first_indexed | 2024-03-06T23:07:00Z |
| format | Journal article |
| id | oxford-uuid:642e0cf9-49f0-470d-81be-b9bb6dc207b7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:07:00Z |
| publishDate | 2020 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | oxford-uuid:642e0cf9-49f0-470d-81be-b9bb6dc207b72022-03-26T18:17:20ZHypoxia induces transcriptional and translational downregulation of the type I IFN pathway in multiple cancer cell typesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:642e0cf9-49f0-470d-81be-b9bb6dc207b7EnglishSymplectic ElementsAmerican Association for Cancer Research2020Miar, AArnaiz, EBridges, EBeedie, SCribbs, APDownes, DJBeagrie, RARehwinkel, JHarris, ALHypoxia is a common phenomenon in solid tumors and is strongly linked to hallmarks of cancer. Recent evidence has shown that hypoxia promotes local immune suppression. Type I IFN supports cytotoxic T lymphocytes by stimulating the maturation of dendritic cells and enhancing their capacity to process and present antigens. However, little is known about the relationship between hypoxia and the type I IFN pathway, which comprises the sensing of double-stranded RNA and DNA (dsRNA/dsDNA) followed by IFNα/β secretion and transcriptional activation of IFN-stimulated genes (ISG). In this study, we determined the effects of hypoxia on the type I IFN pathway in breast cancer and the mechanisms involved. In cancer cell lines and xenograft models, mRNA and protein expressions of the type I IFN pathway were downregulated under hypoxic conditions. This pathway was suppressed at each level of signaling, from the dsRNA sensors RIG-I and MDA5, the adaptor MAVS, transcription factors IRF3, IRF7, and STAT1, and several ISG including RIG-I, IRF7, STAT1, and ADAR-p150. Importantly, IFN secretion was reduced under hypoxic conditions. HIF1α- and HIF2α-mediated regulation of gene expression did not explain most of the effects. However, ATAC-seq data revealed in hypoxia that peaks with STAT1 and IRF3 motifs had decreased accessibility. Collectively, these results indicate that hypoxia leads to an overall downregulation of the type I IFN pathway due to repressed transcription and lower chromatin accessibility in an HIF1/2α-independent manner, which could contribute to immunosuppression in hypoxic tumors. |
| spellingShingle | Miar, A Arnaiz, E Bridges, E Beedie, S Cribbs, AP Downes, DJ Beagrie, RA Rehwinkel, J Harris, AL Hypoxia induces transcriptional and translational downregulation of the type I IFN pathway in multiple cancer cell types |
| title | Hypoxia induces transcriptional and translational downregulation of the type I IFN pathway in multiple cancer cell types |
| title_full | Hypoxia induces transcriptional and translational downregulation of the type I IFN pathway in multiple cancer cell types |
| title_fullStr | Hypoxia induces transcriptional and translational downregulation of the type I IFN pathway in multiple cancer cell types |
| title_full_unstemmed | Hypoxia induces transcriptional and translational downregulation of the type I IFN pathway in multiple cancer cell types |
| title_short | Hypoxia induces transcriptional and translational downregulation of the type I IFN pathway in multiple cancer cell types |
| title_sort | hypoxia induces transcriptional and translational downregulation of the type i ifn pathway in multiple cancer cell types |
| work_keys_str_mv | AT miara hypoxiainducestranscriptionalandtranslationaldownregulationofthetypeiifnpathwayinmultiplecancercelltypes AT arnaize hypoxiainducestranscriptionalandtranslationaldownregulationofthetypeiifnpathwayinmultiplecancercelltypes AT bridgese hypoxiainducestranscriptionalandtranslationaldownregulationofthetypeiifnpathwayinmultiplecancercelltypes AT beedies hypoxiainducestranscriptionalandtranslationaldownregulationofthetypeiifnpathwayinmultiplecancercelltypes AT cribbsap hypoxiainducestranscriptionalandtranslationaldownregulationofthetypeiifnpathwayinmultiplecancercelltypes AT downesdj hypoxiainducestranscriptionalandtranslationaldownregulationofthetypeiifnpathwayinmultiplecancercelltypes AT beagriera hypoxiainducestranscriptionalandtranslationaldownregulationofthetypeiifnpathwayinmultiplecancercelltypes AT rehwinkelj hypoxiainducestranscriptionalandtranslationaldownregulationofthetypeiifnpathwayinmultiplecancercelltypes AT harrisal hypoxiainducestranscriptionalandtranslationaldownregulationofthetypeiifnpathwayinmultiplecancercelltypes |