Adenosine acts through an A3 receptor to prevent the induction of murine anti-CD3-activated killer T cells

Int J Cancer. 2002 May 20;99(3):386-95. doi: 10.1002/ijc.10325.


Adenosine, a purine nucleoside found at high levels in solid tumors, is able to suppress the recognition/adhesion and effector phases of killer lymphocyte-mediated tumor cell destruction. Here, we demonstrate that adenosine, at concentrations that are typically present in the extracellular fluid of solid tumors, exerts a profound inhibitory effect on the induction of mouse cytotoxic T cells, without substantially affecting T-cell viability. T-cell proliferation in response to mitogenic anti-CD3 antibody was impaired in the presence of 10 microM adenosine (plus coformycin to inhibit endogenous adenosine deaminase). Antigen-specific T-cell proliferation was similarly inhibited by adenosine. Anti-CD3-activated killer T (AK-T) cells induced in the presence of adenosine exhibited reduced major histocompatibility complex-unrestricted cytotoxicity against P815 mastocytoma cells in JAM and (51)Cr-release assays. Diminished tumoricidal activity correlated with reduced expression of mRNAs coding for granzyme B, perforin, Fas ligand and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), as well as with diminished Nalpha-CBZ-L-lysine thiobenzylester (BLT) esterase activity. Interleukin-2 and interferon-gamma synthesis by AK-T cells was also inhibited by adenosine. AK-T cells express mRNA coding for A(2A), A(2B) and A(3) receptors, but little or no mRNA coding for A(1) receptors. The inhibitory effect of adenosine on AK-T cell proliferation was blocked by an A(3) receptor antagonist (MRS1191) but not by an A(2) receptor antagonist (3,7-dimethyl-1-propargylxanthine [DMPX]). The A(3) receptor agonists (N(6)-2-(4-aminophenyl)ethyladenosine [APNEA] and N(6)-benzyl-5'-N-ethylcarboxamidoadenosine [N(6)-benzyl-NECA]) also inhibited AK-T cell proliferation. Adenosine, therefore, acts through an A(3) receptor to prevent AK-T cell induction. Tumor-associated adenosine may act through the same mechanism to impair the development of tumor-reactive T cells in cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / metabolism*
  • Adenosine / pharmacology
  • Adenosine Deaminase / metabolism
  • Animals
  • Apoptosis Regulatory Proteins
  • Brain / metabolism
  • CD3 Complex / biosynthesis*
  • Cell Division
  • Cell Survival
  • Cells, Cultured
  • Chromium Radioisotopes / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Interferon-gamma / biosynthesis
  • Interleukin-2 / biosynthesis
  • Killer Cells, Natural / metabolism*
  • Lymphocytes / metabolism
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Purinergic P1 Receptor Antagonists
  • RNA, Messenger / metabolism
  • Receptor, Adenosine A3
  • Receptors, Purinergic P1 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Tetrazolium Salts / pharmacology
  • Theobromine / analogs & derivatives*
  • Theobromine / pharmacology
  • Thiazoles / pharmacology
  • Thymidine / metabolism
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism


  • Apoptosis Regulatory Proteins
  • CD3 Complex
  • Chromium Radioisotopes
  • Interleukin-2
  • Membrane Glycoproteins
  • Purinergic P1 Receptor Antagonists
  • RNA, Messenger
  • Receptor, Adenosine A3
  • Receptors, Purinergic P1
  • TNF-Related Apoptosis-Inducing Ligand
  • Tetrazolium Salts
  • Thiazoles
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • 3,7-dimethyl-1-propargylxanthine
  • Interferon-gamma
  • Adenosine Deaminase
  • thiazolyl blue
  • Adenosine
  • Theobromine
  • Thymidine