THE EXTRACELLULAR FLUID OF SOLID CARCINOMAS CONTAINS IMMUNOSUPPRESSIVE CONCENTRATIONS OF ADENOSINE

The purine nucleoside adenosine (9-beta-D-ribofuranosyladenine) inhibi ts a number of lymphocyte functions irt vitro, including the ability o f activated T lymphocytes and natural killer cells to adhere to and ki ll tumor targets. Solid tumors, such as adenocarcinomas of the lung an d colon, are frequently hypoxic and are, therefore, likely to exhibit increased adenine nucleotide breakdown through the 5'-nucleotidase pat hway, yielding adenosine. We examined whether the concentration of ade nosine in the extracellular fluid of such tumors is adequate to cause immunosuppression. Murine tumors grown in syngeneic hosts or human tum ors grown in immunodeficient nu/nu mice were subjected to microdialysi s, and adenosine levels in the microdialysate were measured by high-pe rformance liquid chromatography. Treatment of the tumor microdialysate s with adenosine deaminase eliminated the adenosine peak. Recovery of adenosine ranged from lj to 29%, depending on the microdialysis probe, and concentrations of adenosine in tumors ranged from 0.2 to 2.4 mu M with a mean of 0.5 mu M. In contrast, the adenosine concentration mea sured s.c. at the same location was 30 +/- 5 nM (mean +/- SE). Inclusi on of the adenosine deaminase inhibitor coformycin (10 mu M) and the a denosine kinase inhibitor 5'-iodotubercidin (0.1 mu M) in the microdia lysis perfusion buffer increased extracellular adenosine concentration in tumors to as high as 13 mu M. These data show that extracellular a denosine levels in solid tumors are sufficient to suppress the local a ntitumor immune response and that interference with pathways of adenos ine metabolism causes marked increases in tumor extracellular adenosin e concentration.