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      • Department of Molecular Biology and Genetics
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      Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment

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      Author(s)
      Cekic, C.
      Linden J.
      Date
      2014
      Source Title
      Cancer Research
      Print ISSN
      0008-5472
      Publisher
      American Association for Cancer Research Inc.
      Volume
      74
      Issue
      24
      Pages
      7239 - 7249
      Language
      English
      Type
      Article
      Item Usage Stats
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      Abstract
      Adenosine A2A receptor (A2AR) blockade enhances innate and adaptive immune responses. However, mouse genetic studies have shown that A2AR deletion does not inhibit the growth of all tumor types. In the current study, we showed that growth rates for ectopic melanoma and bladder tumors are increased in Adora2a-/- mice within 2 weeks of tumor inoculation. A2AR deletion in the host reduced numbers of CD8+ T cells and effector-memory differentiation of all T cells. To examine intrinsic functions in T cells, we generated mice harboring a T-cell-specific deletion of A2AR. In this host strain, tumor-bearing mice displayed increased growth of ectopic melanomas, decreased numbers of tumor-associated T cells, reduced effector-memory differentiation, and reduced antiapoptotic IL7Rα (CD127) expression on antigen-experienced cells. Intratumoral pharmacologic blockade similarly reduced CD8+ T-cell density within tumors in wild-type hosts. We found that A2AR-proficient CD8+ T cells specific for melanoma cells displayed a relative survival advantage in tumors. Thus, abrogating A2AR signaling appeared to reduce IL7R expression, survival, and differentiation of T cells in the tumor microenvironment. One implication of these results is that the antitumor effects of A2AR blockade that can be mediated by activation of cytotoxic T cells may be overcome in some tumor microenvironments as a result of impaired T-cell maintenance and effector-memory differentiation. Thus, our findings imply that the efficacious application of A2AR inhibitors for cancer immunotherapy may require careful dose optimization to prevent activation-induced T-cell death in tumors. ©2014 AACR.
      Keywords
      adenosine A2a receptor
      interleukin 7 receptor
      adoptive transfer
      animal cell
      animal experiment
      animal model
      antigen expression
      Article
      bladder carcinoma
      CD8+ T lymphocyte
      cell density
      cell survival
      controlled study
      cytotoxic T lymphocyte
      flow cytometry
      in vivo study
      lymphocyte differentiation
      lymphocyte function
      melanoma
      melanoma cell
      mouse
      nonhuman
      pharmacological blocking
      protein expression
      regulatory mechanism
      signal transduction
      tumor microenvironment
      wild type
      Permalink
      http://hdl.handle.net/11693/24780
      Published Version (Please cite this version)
      http://dx.doi.org/10.1158/0008-5472.CAN-13-3581
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