title: Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor.
abstract: The A(2A) adenosine receptor plays a critical and non-redundant role in suppressing inflammation at sites of hypoxia and tissue damage. The tumor microenvironment has high levels of adenosine as a result of hypoxia and ectopic expression of enzymes responsible for the generation of extracellular adenosine. Thus, we sought to determine the ability of A(2A) receptor null mice to immunologically reject tumors. We observed that mice lacking the A(2A) adenosine receptor showed significantly delayed growth of lymphoma cells when compared to WT mice. Furthermore, when immunized with a low dose of tumor or with an irradiated GM-CSF-secreting tumor vaccine, A(2A) receptor null mice showed significantly enhanced protection from a subsequent high-dose challenge from both immunogenic and poorly immunogenic tumor lines. This increase in protection was accompanied by an increase in the number of tumor-antigen-specific CD8 T cells at the vaccine-site draining lymph node. Finally, we found that A(2A) receptor null mice displayed more robust anti-tumor responses than WT mice when they were treated with a soluble B7-DC/Fc fusion protein designed to antagonize B7-H1-mediated co-inhibition. This combinatorial immunotherapy strategy could also be recapitulated with pharmacological A(2A) receptor blockade paired with B7-DC/Fc administration. In light of these data, we believe that blockade of the A(2A) adenosine receptor is an attractive target for tumor immunotherapy that synergizes with other immunomodulatory approaches currently in clinical trials.
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. awaickm1@jhmi.edu
authors: Adam T
authors: AT
authors: Waickman
authors: Angela
authors: A
authors: Alme
authors: Liana
authors: L
authors: Senaldi
authors: Paul E
authors: PE
authors: Zarek
authors: Maureen
authors: M
authors: Horton
authors: Jonathan D
authors: JD
authors: Powell
mesh_terms: D000818:Animals; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D043705:Receptor, Adenosine A2A / Q000172:deficiency*; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D043705:Receptor, Adenosine A2A