Targeting the A2A adenosine receptor counteracts immunosuppression in vivo in a mouse model of chronic lymphocytic leukemia

Francesca Arruga, Sara Serra, Nicoletta Vitale, Giulia Guerra, Andrea Papait, Benjamin Baffour Gyau, Francesco Tito, Dimitar Efremov, Tiziana Vaisitti, Silvia Deaglio

Risultato della ricerca: Contributo in rivistaArticolo in rivista


Tumor immunosuppression is a major cause of treatment failure and disease relapse, both in solid tumors and leukemia. Local hypoxia is among the conditions that cause immunosuppression, acting at least in part through the upregulation of extracellular adenosine levels, which potently suppress T-cell responses and skew macrophages towards an M2 phenotype. Hence, there is intense investigation to identify drugs that target this axis. By using the TCL1 adoptive transfer chronic lymphocytic leukemia mouse model, we show that adenosine production and signaling are upregulated in the hypoxic lymphoid niches, where intense colonization of leukemic cells occurs. This leads to a progressive remodeling of the immune system towards tolerance, with expansion of T regulatory cells (Treg), loss of CD8+ T-cell cytotoxicity and differentiation of murine macrophages towards the patrolling (M2-like) subset. In vivo administration of SCH58261, an inhibitor of the A2A adenosine receptor, re-awakens T-cell responses, while limiting Treg expansion, and re-polarizes monocytes towards the inflammatory (M1-like) phenotype. These results show for the first time the in vivo contribution of adenosine signaling to immune tolerance in chronic lymphocytic leukemia, and the translational implication of drugs interrupting this pathway. Although the effects of SCH58261 on leukemic cells are limited, interfering with adenosine signaling may represent an appealing strategy for combination-based therapeutic approaches.
Lingua originaleEnglish
pagine (da-a)1343-1353
Numero di pagine11
Stato di pubblicazionePubblicato - 2021


  • Animals
  • Disease Models, Animal
  • Immune Tolerance
  • Immunosuppression Therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Mice
  • Receptors, Purinergic P1


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