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Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma

par Allard, Bertrand;Jacoberger-Foissac, Célia;Cousineau, Isabelle;Bareche, Yacine ;Buisseret, Laurence ;Chrobak, Pavel;Allard, David;Pommey, Sandra;Ah-Pine, Franck;Duquenne, Sebastien;Picard, Fabien A.;Stagg, John
Référence Cell Reports Medicine, 4, 9, page (101188)
Publication Publié, 2023-09-01

Article révisé par les pairs

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Résumé :

Inhibition of adenosine A2A receptor (A2AR) is a promising approach for cancer immunotherapy currently evaluated in several clinical trials. We here report that anti-obesogenic and anti-inflammatory functions of A2AR, however, significantly restrain hepatocellular carcinoma (HCC) development. Adora2a deletion in mice triggers obesity, non-alcoholic steatohepatitis (NASH), and systemic inflammation, leading to spontaneous HCC and promoting dimethylbenzyl-anthracene (DMBA)- or diethylnitrosamine (DEN)-induced HCC. Conditional Adora2a deletion reveals critical roles of myeloid and hepatocyte-derived A2AR signaling in restraining HCC by limiting hepatic inflammation and steatosis. Remarkably, the impact of A2AR pharmacological blockade on HCC development is dependent on pre-existing NASH. In support of our animal studies, low ADORA2A gene expression in human HCC is associated with cirrhosis, hepatic inflammation, and poor survival. Together, our study uncovers a previously unappreciated tumor-suppressive function for A2AR in the liver and suggests caution in the use of A2AR antagonists in patients with NASH and NASH-associated HCC.