Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development
Menée à l'aide de lignées cellulaires, d'un modèle murin et d'échantillons tumoraux ainsi que d'échantillons tissulaires normaux issus de patients atteints d'un carcinome hépatocellulaire, cette étude met en évidence un mécanisme par lequel le facteur inductible par l'hypoxie, en agissant sur le métabolisme de l'adénosine, favorise le développement et la progression de la maladie
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. Hypoxia promotes adenosine efflux to dampen anti-tumor immune responses and contributes to immune checkpoint inhibitor resistance.