Elsevier

Cellular Immunology

Volume 159, Issue 1, November 1994, Pages 85-93
Cellular Immunology

Regular Article
2-Chloroadenosine Inhibits the MHC-Unrestricted Cytolytic Activity of Anti-CD3-Activated Killer Cells: Evidence for the Involvement of a Non-A1/A2 Cell-Surface Adenosine Receptor

https://doi.org/10.1006/cimm.1994.1297Get rights and content

Abstract

Adenosine is likely to be a frequent constituent of the tumor microenvironment since this purine nucleoside is produced in quantity by hypoxic cells such as those found in the interior of poorly vascularized solid tumors. In this study we show that 2-chloroadenosine (2CA), a stable analogue of adenosine, inhibits, in a dose-dependent fashion, MHC-unrestricted killing of P815 tumor target cells by anti-CD3-activated killer (AK) lymphocytes. 2CA mediates this effect by interfering with the recognition/adhesion phase of cytolysis. Blocking cellular uptake of 2CA with dipyridamole, rather than attenuating the inhibitory effect, potentiated the inhibition of cytolysis, indicating the involvement of a cell-surface receptor. However, neither the A1 receptor antagonist DPCPX, nor the A2 receptor antagonist DMPX were able to block the inhibitory effect of 2CA on AK lymphocyte function. Similarly, the nonselective A1 and A2 receptor antagonists, theophylline and 8-phenyltheophylline, had no effect on 2CA-mediated inhibition of AK cell activity. Taken together, these data provide evidence that 2CA inhibits the cytolytic activity of AK lymphocytes by interacting with a novel non-A1/A2 cell-surface receptor. A similar effect mediated in vivo by tumor-elaborated adenosine may be involved in tumor-associated immunosuppression.

References (0)

Cited by (30)

  • Adenosine receptors and cancer

    2011, Biochimica et Biophysica Acta - Biomembranes
    Citation Excerpt :

    It has been demonstrated that colon adenocarcinoma cells inhibited anti-CD3-activated killer cell induction through the production of a tumor-associated soluble factor that was distinct from transforming growth factor-beta (TGF-β) or prostaglandins [14]. Therefore, adenosine was indicated as a possible inhibitor of killer T-cell activation in the microenvironment of solid tumors [15,16]. Indeed, evaluating the adhesion of murine spleen-derived anti-CD3-activated killer (AK) lymphocytes to syngeneic MCA-38 colon adenocarcinoma cells, it was found that adenosine reduced adhesion by up to 60% [17].

  • Adenosine stimulation of the proliferation of colorectal carcinoma cell lines: Roles of cell density and adenosine metabolism

    2003, Biochemical Pharmacology
    Citation Excerpt :

    Under hypoxic conditions, as in tumors in vivo, the generation rate of adenosine through AMP nucleotidase would be much higher, shifting the major role in intracellular breakdown over to ADA, which has a much higher Km (70 μM) but far greater capacity for adenosine metabolism than AK [56]. We have previously shown that adenosine can dramatically suppress the anti-tumor immune response [12–17]. Adenosine may also act to promote tumor cell migration [57] and stimulate angiogenesis [58,59], as well as increase intratumoral blood flow [60], and confer protection against radiotherapy [61].

  • 2 The Adenosine A<inf>3</inf> Receptor and its Ligands

    2001, Progress in Medicinal Chemistry
View all citing articles on Scopus
View full text