腺苷
腺苷激酶
癌症研究
肿瘤微环境
腺苷A3受体
嘌呤能信号
腺苷受体
一磷酸腺苷
缺氧(环境)
免疫系统
化学
生物
药理学
免疫学
受体
腺苷脱氨酶
内分泌学
生物化学
兴奋剂
有机化学
氧气
作者
Jacinth Wing‐Sum Cheu,Dah Ming Chiu,Kenneth Kin Leung Kwan,Chunxue Yang,Vincent Wai‐Hin Yuen,Chi Ching Goh,Noreen Nog-Qin Chui,Wei Shen,Cheuk‐Ting Law,Qidong Li,Misty Shuo Zhang,Macus Hao-Ran Bao,Bowie Po‐Yee Wong,Cerise Yuen‐Ki Chan,Cindy Xinqi Liu,Grace Fu-Wan Sit,Zher Yee Ooi,Haijing Deng,Aki Pui‐Wah Tse,Irene Oi Lin Ng,Carmen Chak‐Lui Wong
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2023-05-05
卷期号:9 (18)
被引量:6
标识
DOI:10.1126/sciadv.ade5111
摘要
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.
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