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

  • Cell Rep Med. 2023 Sep 19;4(9):101188. doi: 10.1016/j.xcrm.2023.101188.
Bertrand Allard  1 ,  Célia Jacoberger-Foissac  1 ,  Isabelle Cousineau  1 ,  Yacine Bareche  1 ,  Laurence Buisseret  2 ,  Pavel Chrobak  1 ,  David Allard  1 ,  Sandra Pommey  1 ,  Franck Ah-Pine  3 ,  Sebastien Duquenne  3 ,  Fabien Picard  4 ,  John Stagg  5
Affiliations
  • 1. Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, QC, Canada; Faculté de Pharmacie, Université de Montréal, Montreal, QC, Canada.
  • 2. Institut Jules Bordet, Bruxelles, Belgium.
  • 3. Department of Pathology, CHU Sud Réunion, Saint-Pierre, France.
  • 4. Montréal Heart Institute, Cardiology Department, Université de Montréal, Montreal, QC, Canada; Hopital Cochin, Cardiology Department, Université de Paris, Paris, France.
  • 5. Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, QC, Canada; Faculté de Pharmacie, Université de Montréal, Montreal, QC, Canada. Electronic address: [email protected].
PMID: 37729873 DOI: 10.1016/j.xcrm.2023.101188
Abstract

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.

Keywords
A2A receptor; HCC; NAFLD; NASH; adenosine; cancer; immuno-oncology; inflammation.
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