2. Academic Validation
  3. Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma

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

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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