Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment
Date
2014Source Title
Cancer Research
Print ISSN
0008-5472
Publisher
American Association for Cancer Research Inc.
Volume
74
Issue
24
Pages
7239 - 7249
Language
English
Type
ArticleItem 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 receptorinterleukin 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