Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment

Date
2014
Authors
Cekic, C.
Linden J.
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Source Title
Cancer Research
Print ISSN
0008-5472
Electronic ISSN
Publisher
American Association for Cancer Research Inc.
Volume
74
Issue
24
Pages
7239 - 7249
Language
English
Type
Article
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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.

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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
Citation
Published Version (Please cite this version)