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Cancer Res. 2014 Dec 15;74(24):7239-49. doi: 10.1158/0008-5472.CAN-13-3581. Epub 2014 Oct 23.

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

Author information

1
Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California. Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
2
Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California. jlinden@liai.org.

Abstract

Adenosine A(2A) receptor (A(2A)R) blockade enhances innate and adaptive immune responses. However, mouse genetic studies have shown that A(2A)R 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. A(2A)R 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 A(2A)R. 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 A(2A)R-proficient CD8(+) T cells specific for melanoma cells displayed a relative survival advantage in tumors. Thus, abrogating A(2A)R 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 A(2A)R 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 A(2A)R inhibitors for cancer immunotherapy may require careful dose optimization to prevent activation-induced T-cell death in tumors.

PMID:
25341542
PMCID:
PMC4459794
DOI:
10.1158/0008-5472.CAN-13-3581
[Indexed for MEDLINE]
Free PMC Article

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