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G_s Protein-Coupled Adenosine Receptor Signaling and Lytic Function of Activated NK Cells¹

Tatiana Raskovalova^*, Xiaojun Huang^*, Michail Sitkovsky, Lefteris C. Zacharia, Edwin K. Jackson and Elieser Gorelik^2,*

^* Department of Pathology and University of Pittsburgh Cancer Institute, Department of Pharmacology and Medicine and Center for Clinical Pharmacology, University of Pittsburgh, Pittsburgh, PA 15213; and New England Inflammation and Tissue Damage Institute, Northeastern University, Boston, MA 02115

The effect of adenosine and its analogues on the cytotoxic activity of IL-2-activated NK cells was investigated. Adenosine is an endogenous ligand for four different adenosine receptor (AdoR) subtypes (AdoRA₁, AdoRA_2A, AdoRA_2B, and AdoRA₃). Increased concentrations of adenosine were found in ascites of MethA sarcoma or in culture medium of 3LL Lewis lung carcinoma growing under hypoxic conditions. We hypothesize that intratumor adenosine impairs the ability of lymphokine-activated killer (LAK) cells to kill tumor cells. The effect of AdoR engagement on LAK cells cytotoxic activity was analyzed using AdoR agonists and antagonists as well as LAK cells generated from AdoR knockout mice. Adenosine and its analogues efficiently inhibited the cytotoxic activity of LAK cells. CGS21680 (AdoRA_2A agonist) and 5-N-ethylcarboxamide adenosine (NECA) (AdoRA_2A/ADoRA_2B agonist) inhibited LAK cell cytotoxicity in parallel with their ability to increase cAMP production. The inhibitory effects of stable adenosine analog 2-chloroadenosine (CADO) and AdoRA₂ agonists were blocked by AdoRA₂ antagonist ZM 241385. Adenosine and its analogues impair LAK cell function by interfering with both perforin-mediated and Fas ligand-mediated killing pathways. Studies with LAK cells generated from AdoRA₁^–/– and AdoRA₃^–/– mice ruled out any involvement of these AdoRs in the inhibitory effects of adenosine. LAK cells with genetically disrupted AdoRA_2A were resistant to the inhibitory effects of adenosine, CADO and NECA. However, with extremely high concentrations of CADO or NECA, mild inhibition of LAK cytotoxicity was observed that was probably mediated via AdoRA_2B signaling. Thus, by using pharmacological and genetic blockage of AdoRs, our results clearly indicate the prime importance of cAMP elevating AdoR2A in the inhibitory effect of adenosine on LAK cell cytotoxicity. The elevated intratumor levels of adenosine might inhibit the antitumor effects of activated NK cells.

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