Journal article
A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment
Cancer Research, Vol.78(4), pp.1003-1016
2017
Abstract
Extracellular adenosine is a key immunosuppressive metabolite that restricts activation of cytotoxic lymphocytes and impairs antitumor immune responses. Here, we show that engagement of A2A adenosine receptor (A2AR) acts as a checkpoint that limits the maturation of natural killer (NK) cells. Both global and NK-cell–specific conditional deletion of A2AR enhanced proportions of terminally mature NK cells at homeostasis, following reconstitution, and in the tumor microenvironment. Notably, A2AR-deficient, terminally mature NK cells retained proliferative capacity and exhibited heightened reconstitution in competitive transfer assays. Moreover, targeting A2AR specifically on NK cells also improved tumor control and delayed tumor initiation. Taken together, our results establish A2AR-mediated adenosine signaling as an intrinsic negative regulator of NK-cell maturation and antitumor immune responses. On the basis of these findings, we propose that administering A2AR antagonists concurrently with NK cell–based therapies may heighten therapeutic benefits by augmenting NK cell–mediated antitumor immunity.
Details
- Title
- A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment
- Authors/Creators
- A. Young (Author/Creator) - QIMR Berghofer Medical Research InstituteS.F. Ngiow (Author/Creator) - University of PennsylvaniaY. Gao (Author/Creator) - QIMR Berghofer Medical Research InstituteA-M Patch (Author/Creator) - QIMR Berghofer Medical Research InstituteD.S. Barkauskas (Author/Creator) - QIMR Berghofer Medical Research InstituteM. Messaoudene (Author/Creator) - Institut Gustave RoussyG. Lin (Author/Creator) - La Jolla Institute for ImmunologyJ.D. Coudert (Author/Creator) - The University of Western AustraliaK.A. Stannard (Author/Creator) - QIMR Berghofer Medical Research InstituteL. Zitvogel (Author/Creator) - Institut Gustave RoussyM.A. Degli-Esposti (Author/Creator) - The University of Western AustraliaE. Vivier (Author/Creator) - Centre d’Immunologie de Marseille-LuminyN. Waddell (Author/Creator) - QIMR Berghofer Medical Research InstituteJ. Linden (Author/Creator) - La Jolla Institute for ImmunologyN.D. Huntington (Author/Creator) - The University of MelbourneF. Souza-Fonseca-Guimaraes (Author/Creator) - The University of MelbourneM.J. Smyth (Author/Creator) - QIMR Berghofer Medical Research Institute
- Publication Details
- Cancer Research, Vol.78(4), pp.1003-1016
- Publisher
- American Association for Cancer Research
- Identifiers
- 991005543722907891
- Copyright
- © 2018 by the American Association for Cancer Research
- Murdoch Affiliation
- Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
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- Citation topics
- 1 Clinical & Life Sciences
- 1.159 Membrane Channels & Receptors
- 1.159.576 Adenosine Signaling
- Web Of Science research areas
- Oncology
- ESI research areas
- Clinical Medicine