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Adenosine acts through a novel extracellular receptor to inhibit granule exocytosis by natural killer cells
B A Williams1, A Manzer, J Blay
1Department of Microbiology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Abstract:
Adenosine concentrations in solid tumors are elevated as a result of altered metabolism by hypoxic cancer cells within the tumor microenvironment. In this study we show that adenosine inhibits mouse natural killer (NK) cell function by interfering with the process of granule exocytosis. Adenosine, at concentrations ranging from 5-25 microM, had a marked inhibitory effect on granule exocytosis by mouse spleen cells stimulated with phorbol myristate acetate and ionomycin. Selective depletion of spleen cell subsets by antibody and complement treatments established that granule exocytosis was mediated by NK cells. Blocking the cellular uptake of adenosine with NBTI or dilazep failed to prevent the inhibitory effect of adenosine, indicating the involvement of a cell-surface receptor. However, adenosine-induced inhibition of granule exocytosis was not blocked by the nonselective A1 and A2 receptor antagonists theophylline and 8-phenyltheophylline, the A1 receptor antagonist DPCPX, or the A2 receptor antagonist DMPX. In addition, the A3 receptor agonists APNEA and NECA failed to affect granule exocytosis. Taken together, these data provide evidence that adenosine inhibits NK cell granule exocytosis by interacting with a novel extracellular receptor. A similar inhibitory effect of tumor-elaborated adenosine on the function of NK cells and other cytotoxic lymphocytes may contribute to tumor survival in the face of host cell-mediated immune defenses.
Insights
Tumor cells release adenosine, which impairs natural killer (NK) cell function by blocking granule release. This occurs via a novel cell-surface receptor, potentially aiding tumor immune evasion.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Elevated adenosine in solid tumors stems from altered cancer cell metabolism under hypoxia.
- Tumor microenvironment conditions can influence immune cell function and anti-tumor responses.
Purpose of the Study:
- To investigate the mechanism by which adenosine affects natural killer (NK) cell function.
- To identify the specific receptor involved in adenosine-mediated inhibition of NK cell activity.
Main Methods:
- Assessed the impact of varying adenosine concentrations on mouse spleen cell granule exocytosis.
- Utilized antibody and complement treatments to deplete specific spleen cell subsets and identify the effector cells.
- Tested the effects of adenosine uptake blockers, known receptor antagonists, and agonists to elucidate the signaling pathway.
Main Results:
- Adenosine significantly inhibited granule exocytosis in NK cells at concentrations of 5-25 microM.
- Inhibition was independent of adenosine cellular uptake, suggesting a cell-surface receptor interaction.
- Standard antagonists for A1, A2, and A3 adenosine receptors, as well as specific agonists, did not block the inhibitory effect.
Conclusions:
- Adenosine inhibits NK cell granule exocytosis through a previously unidentified extracellular receptor.
- This interaction may represent a mechanism for tumor immune evasion by suppressing cytotoxic lymphocyte activity.