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Inhibition of Cytokine Production and Cytotoxic Activity of Human Antimelanoma Specific CD8⁺ and CD4⁺ T Lymphocytes by Adenosine-Protein Kinase A Type I Signaling

Departments of ¹ Pathology, ² Immunology, ³ Pharmacology, and ⁴ Medicine, and ⁵ Center for Clinical Pharmacology, School of Medicine, University of Pittsburgh and ⁶ University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Requests for reprints: Elieser Gorelik, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Room 1.46, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-3217; Fax: 1-412-624-7736; E-mail: gorelik{at}pitt.edu.

The goal of this study was to investigate the effects of adenosine and its stable analogue 2-chloroadenosine (CADO) on the cytotoxic activity and cytokine production by human antimelanoma specific CD8⁺ and CD4⁺ T-helper type 1 (Th1) clones. The cytotoxic activity of CD8⁺ T cells was inhibited by adenosine and CADO. Using Lab MAP multiplex technology, we found that adenosine inhibits production of various cytokines and chemokines by CD8⁺ and CD4⁺ T cells. Studies with CGS21680, a specific agonist of adenosine A_2A receptor (AdoRA_2A), and ZM241385, an AdoRA₂-selective antagonist, indicate that the inhibitory effects of adenosine are mediated via cyclic AMP (cAMP)–elevating AdoRA_2A, leading to protein kinase A (PKA) activation. Using cAMP analogues with different affinities for the A and B sites of the regulatory subunits of PKAI and PKAII, we found that activation of PKAI, but not of PKAII, mimicked the inhibitory effects of adenosine on T-cell cytotoxic activity and cytokine production. Inhibitors of the PKA catalytic subunits (H89 and PKA inhibitor peptide 14–22) failed to abrogate the inhibitory effects of CADO. In contrast, Rp-8-Br-cAMPS that antagonizes binding of cAMP to the regulatory I subunit and PKA activation was efficient in blocking the inhibitory effect of adenosine on the functional activity of T cells. Our findings on the ability of adenosine to inhibit the effector function of antimelanoma specific T cells suggest that intratumor-produced adenosine could impair the function of tumor-infiltrating T lymphocytes. Thus, blocking the inhibitory activity of tumor-produced adenosine might represent a new strategy for improvement of cancer immunotherapy. [Cancer Res 2007;67(12):5949–56]

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