Journal
CANCER RESEARCH
Volume 78, Issue 4, Pages 1003-1016Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-2826
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Funding
- Cancer Council Queensland Ph.D. fellowship
- National Health and Medical Research Council of Australia (NHMRC) [1078671, 1120887]
- Susan G. Komen Program [IIR12221504]
- Cancer Research Institute Clinical Strategy Team Grant
- National Institutes of Health [R01 HL111969]
- NHMRC C.J. Martin Fellowship [1111469]
- NHMRC Early Career Fellowship [1088703]
- National Breast Cancer Foundation (NBCF) Fellowship [PF-15-008]
- Priority-driven Collaborative Cancer Research Scheme [1120725]
- Cure Cancer Australia
- Cancer Australia
- NH&MRC Project Grant
- Melanoma Research Grant from the Harry J Lloyd Charitable Trust
- Cancer Research Institute Clinical and Laboratory Integration Program (CLIP) grant
- National Breast Cancer Foundation [PF-15-008] Funding Source: researchfish
- National Health and Medical Research Council of Australia [1088703, 1120887, 1111469] Funding Source: NHMRC
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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. Significance: Ablating adenosine signaling is found to promote natural killer cell maturation and antitumor immunity and reduce tumor growth. (C) 2017 AACR.
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