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A2AR Adenosine Signaling Suppresses Natural Killer Cell Maturation in the Tumor Microenvironment
Arabella Young1,2, Shin Foong Ngiow1,2,3, Yulong Gao1,2
1Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
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.Significance: Ablating adenosine signaling is found to promote natural killer cell maturation and antitumor immunity and reduce tumor growth. Cancer Res; 78(4); 1003-16. ©2017 AACR.
Insights
Blocking the A2A adenosine receptor (A2AR) promotes natural killer (NK) cell maturation and enhances antitumor immunity. Targeting A2AR improves tumor control, suggesting A2AR antagonists could boost NK cell-based cancer therapies.
Area of Science:
- Immunology
- Cancer Biology
- Cellular and Molecular Medicine
Background:
- Extracellular adenosine, an immunosuppressive metabolite, inhibits cytotoxic lymphocytes and impairs antitumor immunity.
- The A2A adenosine receptor (A2AR) is implicated in immune regulation, but its specific role in natural killer (NK) cell maturation is not fully understood.
Purpose of the Study:
- To investigate the role of A2AR in regulating NK cell maturation and antitumor immune responses.
- To determine if targeting A2AR can enhance NK cell-mediated antitumor immunity.
Main Methods:
- Utilized global and NK-cell-specific conditional deletion of A2AR in mouse models.
- Assessed NK cell proportions, maturation status, proliferative capacity, and reconstitution potential.
- Evaluated tumor control and initiation in A2AR-targeted models.
Main Results:
- Deletion of A2AR enhanced the proportion of terminally mature NK cells in various conditions, including homeostasis and the tumor microenvironment.
- A2AR-deficient NK cells showed retained proliferative capacity and improved reconstitution.
- Targeting A2AR on NK cells improved tumor control and delayed tumor initiation.
Conclusions:
- A2AR signaling intrinsically suppresses NK cell maturation and antitumor immunity.
- A2AR antagonists represent a potential therapeutic strategy to augment NK cell-mediated antitumor responses when used with NK cell-based therapies.
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