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Article: Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development

TitleHypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development
Authors
Issue Date5-May-2023
PublisherAmerican Association for the Advancement of Science
Citation
Science Advances, 2023, v. 9, n. 18 How to Cite?
Abstract

Hypoxia-induced adenosine creates an immunosuppressive tumor microenvironment (TME) and dampens the efficacy of immune checkpoint inhibitors (ICIs). We found that hypoxia-inducible factor 1 (HIF-1) orchestrates adenosine efflux through two steps in hepatocellular carcinoma (HCC). First, HIF-1 activates transcriptional repressor MXI1, which inhibits adenosine kinase (ADK), resulting in the failure of adenosine phosphorylation to adenosine monophosphate. This leads to adenosine accumulation in hypoxic cancer cells. Second, HIF-1 transcriptionally activates equilibrative nucleoside transporter 4, pumping adenosine into the interstitial space of HCC, elevating extracellular adenosine levels. Multiple in vitro assays demonstrated the immunosuppressive role of adenosine on T cells and myeloid cells. Knockout of ADK in vivo skewed intratumoral immune cells to protumorigenic and promoted tumor progression. Therapeutically, combination treatment of adenosine receptor antagonists and anti–PD-1 prolonged survival of HCC-bearing mice. We illustrated the dual role of hypoxia in establishing an adenosine-mediated immunosuppressive TME and offered a potential therapeutic approach that synergizes with ICIs in HCC. 


Persistent Identifierhttp://hdl.handle.net/10722/331880
ISSN
2023 Impact Factor: 11.7
2023 SCImago Journal Rankings: 4.483
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorCheu, JWS-
dc.contributor.authorChiu, DKC-
dc.contributor.authorKwan, KKL-
dc.contributor.authorYang, CX-
dc.contributor.authorYuen, VWH-
dc.contributor.authorGoh, CC-
dc.contributor.authorChui, NNQ-
dc.contributor.authorShen, W-
dc.contributor.authorLaw, CT-
dc.contributor.authorLi, QD-
dc.contributor.authorZhang, MS-
dc.contributor.authorBao, MHR-
dc.contributor.authorWong, BPY-
dc.contributor.authorChan, CYK-
dc.contributor.authorLiu, CX-
dc.contributor.authorSit, GFW-
dc.contributor.authorOoi, ZY-
dc.contributor.authorDeng, HJ-
dc.contributor.authorTse, APW-
dc.contributor.authorNg, IOL-
dc.contributor.authorWong, CCL-
dc.date.accessioned2023-09-28T04:59:19Z-
dc.date.available2023-09-28T04:59:19Z-
dc.date.issued2023-05-05-
dc.identifier.citationScience Advances, 2023, v. 9, n. 18-
dc.identifier.issn2375-2548-
dc.identifier.urihttp://hdl.handle.net/10722/331880-
dc.description.abstract<p>Hypoxia-induced adenosine creates an immunosuppressive tumor microenvironment (TME) and dampens the efficacy of immune checkpoint inhibitors (ICIs). We found that hypoxia-inducible factor 1 (HIF-1) orchestrates adenosine efflux through two steps in hepatocellular carcinoma (HCC). First, HIF-1 activates transcriptional repressor MXI1, which inhibits adenosine kinase (ADK), resulting in the failure of adenosine phosphorylation to adenosine monophosphate. This leads to adenosine accumulation in hypoxic cancer cells. Second, HIF-1 transcriptionally activates equilibrative nucleoside transporter 4, pumping adenosine into the interstitial space of HCC, elevating extracellular adenosine levels. Multiple in vitro assays demonstrated the immunosuppressive role of adenosine on T cells and myeloid cells. Knockout of ADK in vivo skewed intratumoral immune cells to protumorigenic and promoted tumor progression. Therapeutically, combination treatment of adenosine receptor antagonists and anti–PD-1 prolonged survival of HCC-bearing mice. We illustrated the dual role of hypoxia in establishing an adenosine-mediated immunosuppressive TME and offered a potential therapeutic approach that synergizes with ICIs in HCC.<span> </span></p>-
dc.languageeng-
dc.publisherAmerican Association for the Advancement of Science-
dc.relation.ispartofScience Advances-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleHypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development-
dc.typeArticle-
dc.identifier.doi10.1126/sciadv.ade5111-
dc.identifier.scopuseid_2-s2.0-85159555773-
dc.identifier.volume9-
dc.identifier.issue18-
dc.identifier.eissn2375-2548-
dc.identifier.isiWOS:000988268100011-
dc.identifier.issnl2375-2548-

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