Academic Journal
Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development
| العنوان: | Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development |
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| المؤلفون: | Cheu, Jacinth Wing-Sum, Chiu, David Kung-Chun, Kwan, Kenneth Kin-Leung, Yang, Chunxue, Yuen, Vincent Wai-Hin, Goh, Chi Ching, Chui, Noreen Nog-Qin, Shen, Wei, Law, Cheuk-Ting, Li, Qidong, Zhang, Misty Shuo, Bao, Macus Hao-Ran, Wong, Bowie Po-Yee, Chan, Cerise Yuen-Ki, Liu, Cindy Xinqi, Sit, Grace Fu-Wan, Ooi, Zher Yee, Deng, Haijing, Tse, Aki Pui-Wah, Ng, Irene Oi-Lin, Wong, Carmen Chak-Lui |
| المصدر: | Science Advances ; volume 9, issue 18 ; ISSN 2375-2548 |
| بيانات النشر: | American Association for the Advancement of Science (AAAS) |
| سنة النشر: | 2023 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1126/sciadv.ade5111 |
| الاتاحة: | http://dx.doi.org/10.1126/sciadv.ade5111 https://www.science.org/doi/pdf/10.1126/sciadv.ade5111 |
| رقم الانضمام: | edsbas.6E59FDE |
| قاعدة البيانات: | BASE |
| DOI: | 10.1126/sciadv.ade5111 |
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