2-CHLOROADENOSINE INHIBITS THE MHC-UNRESTRICTED CYTOLYTIC ACTIVITY OFANTI-CD3-ACTIVATED KILLER-CELLS - EVIDENCE FOR THE INVOLVEMENT OF A NON-A(1) A(2) CELL-SURFACE ADENOSINE RECEPTOR/

Adenosine is likely to be a frequent constituent of the tumor microenv ironment since this purine nucleoside is produced in quantity by hypox ic cells such as those found in the interior of poorly vascularized so lid tumors. In this study we show that 2-chloroadenosine (2CA), a stab le analogue of adenosine, inhibits, in a dose-dependent fashion, MHC-u nrestricted killing of P815 tumor target cells by anti-CD3-activated k iller (AK) lymphocytes. 2CA mediates this effect by interfering with t he recognition/adhesion phase of cytolysis. Blocking cellular uptake o f 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 Al receptor antagonis t DPCPX, nor the Al receptor antagonist DMPX were able to block the in hibitory effect of 2CA on AK lymphocyte function. Similarly, the nonse lective A(1) and A(2) receptor antagonists, theophylline and 8-phenylt heophylline, had no effect on 2CA-mediated inhibition of AK cell activ ity. Taken together, these data provide evidence that 2CA inhibits the cytolytic activity of AK lymphocytes by interacting with a novel non- A(1)/A(2) cell-surface receptor. A similar effect mediated in vivo by tumor-elaborated adenosine may be involved in tumor-associated immunos uppression. (C) 1994 Academic Press, Inc.