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

Haematologica. 2021 May 1;106(5):1343-1353. doi: 10.3324/haematol.2019.242016.

Abstract

Tumor immunosuppression is a major cause for 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 CLL 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 (Tregs), loss of CD8+ T cell cytotoxicity and differentiation of murine macrophages towards the patrolling (M2-like) subset. In vivo administration of SCH58261, an inhibitor the A2A adenosine receptor, re-awakens T cell responses, while limiting Tregs 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 CLL, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Immune Tolerance
  • Immunosuppression
  • Leukemia, Lymphocytic, Chronic, B-Cell* / drug therapy
  • Mice
  • Receptors, Purinergic P1

Substances

  • Receptors, Purinergic P1

Grant support

FundingThis work was supported by Italian Institute for Genomic Medicine institutional funds, by the Associazione Italiana per la Ricerca sul Cancro AIRC (IG17314 to SD), by the Gilead Fellowship Program 2018 (by the ITN INTEGRATA program, grant agreement 813284 to SD), by the Italian Ministry of Health (GR-2016-02364298 to TV), by the Ministry of Education, University and Research-MIUR “Progetto Strategico di Eccellenza Dipartimentale” (#D15D18000410001 to SD in part through funds to the Department of Medical Sciences, University of Turin); and by the Ministry of Education, University and Research-MIUR PRIN project (2017CBNCYT to SD).