Enhancement of tumor immunotherapy by deletion of the A 2A adenosine receptor

Adam T. Waickman, Angela Alme, Liana Senaldi, Paul E. Zarek, Maureen Horton, Jonathan D. Powell

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)917-926
Number of pages10
JournalCancer Immunology, Immunotherapy
Volume61
Issue number6
DOIs
StatePublished - Jun 2012

Keywords

  • A2a Adenosine receptor
  • B7-DC
  • Co-inhibition
  • T cell
  • Tumor
  • Vaccine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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