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

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dc.citation.epage7249en_US
dc.citation.issueNumber24en_US
dc.citation.spage7239en_US
dc.citation.volumeNumber74en_US
dc.contributor.authorCekic, C.en_US
dc.contributor.authorLinden J.en_US
dc.date.accessioned2016-02-08T10:34:16Z
dc.date.available2016-02-08T10:34:16Z
dc.date.issued2014en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractAdenosine 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.en_US
dc.identifier.doi10.1158/0008-5472.CAN-13-3581en_US
dc.identifier.issn0008-5472
dc.identifier.urihttp://hdl.handle.net/11693/24780
dc.language.isoEnglishen_US
dc.publisherAmerican Association for Cancer Research Inc.en_US
dc.relation.isversionofhttp://dx.doi.org/10.1158/0008-5472.CAN-13-3581en_US
dc.source.titleCancer Researchen_US
dc.subjectadenosine A2a receptoren_US
dc.subjectinterleukin 7 receptoren_US
dc.subjectadoptive transferen_US
dc.subjectanimal cellen_US
dc.subjectanimal experimenten_US
dc.subjectanimal modelen_US
dc.subjectantigen expressionen_US
dc.subjectArticleen_US
dc.subjectbladder carcinomaen_US
dc.subjectCD8+ T lymphocyteen_US
dc.subjectcell densityen_US
dc.subjectcell survivalen_US
dc.subjectcontrolled studyen_US
dc.subjectcytotoxic T lymphocyteen_US
dc.subjectflow cytometryen_US
dc.subjectin vivo studyen_US
dc.subjectlymphocyte differentiationen_US
dc.subjectlymphocyte functionen_US
dc.subjectmelanomaen_US
dc.subjectmelanoma cellen_US
dc.subjectmouseen_US
dc.subjectnonhumanen_US
dc.subjectpharmacological blockingen_US
dc.subjectprotein expressionen_US
dc.subjectregulatory mechanismen_US
dc.subjectsignal transductionen_US
dc.subjecttumor microenvironmenten_US
dc.subjectwild typeen_US
dc.titleAdenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironmenten_US
dc.typeArticleen_US
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