Teresa Reynolds's research while affiliated with Dalhousie University and other places

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.

Adoptive immunotherapy with lymphokine-activated killer (LAK) cells has shown some promise in the treatment of certain cancers that are unresponsive to conventional treatment approaches. However, colon adenocarcinomas tend to respond poorly to LAK therapy, possibly as a result of tumor-induced immunosupprression. Recently, in vivo administration of anti-CD3 antibody has been shown to induce mouse T lymphocytes to mediate major-histocompatibility-complex(MHC)-unrestricted tumoricidal activity which is distinet from natural-killer-cell-derived LAK activity. It has therfore been suggested that anti-CD3 therapy may find application in tumor immunotherapy in humans. However, the effectiveness of anti-CD3-activated killer cell induction within the environment found in the vicinity of colon adenocarcinoma cells has not been evaluated. The present report demonstrates that colon cancer cells of human (HT-29) and mouse (MCA-38) origin markedly inhibit the generation of activated killer cells in murine spleen cell cultures. DNA synthesis and interleukin-2 production by spleen cells following stimulation with anti-CD3 antibody are also profoundly depressed in the presence of MCA-38 and HT-29 adenocarcinoma cells. MCA-38- and HT-29-mediated inhibition of activated killer cell development is exerted through the production of a tumor-associated soluble factor that is distinct from transforming growth factor or prostaglandins. Local immunosupression associated with sites of tumor growth may therefore represent a major obstacle to successful anti-CD3 immunotherapy of certain colon adenocarcinomas.