ADENOSINE INHIBITS THE ADHESION OF ANTI-CD3-ACTIVATED KILLER LYMPHOCYTES TO ADENOCARCINOMA CELLS THROUGH AN A(3) RECEPTOR

We have investigated the hypothesis that adenosine, a purine nucleosid e produced within hypoxic regions of solid tumors, may interfere with the recognition of tumor cells by cytolytic effector cells of the immu ne system. We measured the adhesion of murine spleen-derived anti-CD3- activated killer (AK) lymphocytes to syngeneic MCA-38 colon adenocarci noma cells in a model system. Adenosine, in the presence of the adenos ine deaminase inhibitor coformycin to prevent the breakdown of adenosi ne, inhibited adhesion by up to 60%. The inhibitory effect of adenosin e was exerted on the AK cells and not on the MCA-38 targets. The respo nse to adenosine was generated at the cell surface, since the inhibiti on of adhesion was not abrogated by S-(4-nitrobenzyl)-6-thioinosine or dipyridamole, which block adenosine uptake. The inhibition of adhesio n due to adenosine was not blocked by either the A(1) receptor antagon ist 8-cyclopentyl-1,3-dipropylxanthine or the A(2) receptor antagonist 3,7-dimethyl-1-propargylxanthine. This suggested that non-A(1), A(2) receptor might be involved. The relative order of potencies of adenosi ne and common analogues was: 5'-N-ethylcarboxamidoadenosine = adenosin e = (R)-phenylisopropyladenosine > N-6-cyclopentyladenosine > 2-chloro -N-6-cyclopentyladenosine = 2-p-(2-carboxyethyl)phenethylamino-5'-N-et hyl- carboxamidoadenosine. This agonist potency profile was again inco nsistent with either the A(1) or the A(2) receptor subtype but indicat ed that the recently described A(3) receptor subtype might be responsi ble for the inhibition of adhesion. Consistent with this suggestion, a minophenylethyladenosine, an adenosine analogue that binds with high a ffinity to A(3) receptors, inhibited the adhesion of AK cells to MCA-3 8 tumor eels with high potency (50% inhibitory concentration approxima te to 1 nM). Adenosine, therefore, interferes with the AK cell recogni tion of colorectal tumor targets by acting through an A(3) receptor on the effector cells. We suggest that this mechanism of immunosuppressi on, secondary to tissue hypoxia, may be important in the resistance of colorectal and other solid cancers to immunotherapy.