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The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine
J Blay1, T D White, D W Hoskin
1Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. jblay@is.dal.ca
Abstract:
The purine nucleoside adenosine (9-beta-D-ribofuranosyladenine) inhibits a number of lymphocyte functions in vitro, including the ability of activated T lymphocytes and natural killer cells to adhere to and kill tumor targets. Solid tumors, such as adenocarcinomas of the lung and colon, are frequently hypoxic and are, therefore, likely to exhibit increased adenine nucleotide breakdown through the 5'-nucleotidase pathway, yielding adenosine. We examined whether the concentration of adenosine in the extracellular fluid of such tumors is adequate to cause immunosuppression. Murine tumors grown in syngeneic hosts or human tumors grown in immunodeficient nu/nu mice were subjected to microdialysis, and adenosine levels in the microdialysate were measured by high-performance liquid chromatography. Treatment of the tumor microdialysates with adenosine deaminase eliminated the adenosine peak. Recovery of adenosine ranged from 15 to 29%, depending on the microdialysis probe, and concentrations of adenosine in tumors ranged from 0.2 to 2.4 microM with a mean of 0.5 microM. In contrast, the adenosine concentration measured s.c. at the same location was 30 +/- 5 nM (mean +/- SE). Inclusion of the adenosine deaminase inhibitor coformycin (10 microM) and the adenosine kinase inhibitor 5'-iodotubercidin (0.1 microM) in the microdialysis perfusion buffer increased extracellular adenosine concentration in tumors to as high as 13 microM. These data show that extracellular adenosine levels in solid tumors are sufficient to suppress the local antitumor immune response and that interference with pathways of adenosine metabolism causes marked increases in tumor extracellular adenosine concentration.
Insights
High adenosine levels in solid tumors suppress the immune system. Inhibiting adenosine metabolism significantly increases tumor adenosine, suggesting a target for cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Adenosine, a purine nucleoside, inhibits lymphocyte functions crucial for anti-tumor immunity.
- Solid tumors, often hypoxic, generate adenosine via nucleotide breakdown, potentially causing local immunosuppression.
Purpose of the Study:
- To investigate extracellular adenosine concentrations in solid tumors.
- To determine if tumor adenosine levels are sufficient to suppress anti-tumor immune responses.
- To assess the impact of interfering with adenosine metabolism on tumor adenosine levels.
Main Methods:
- Microdialysis was used to measure extracellular adenosine in murine and human solid tumors.
- High-performance liquid chromatography (HPLC) quantified adenosine levels.
- Adenosine deaminase and inhibitors of adenosine metabolism (coformycin, 5'-iodotubercidin) were employed.
Main Results:
- Extracellular adenosine concentrations in tumors ranged from 0.2 to 2.4 microM (mean 0.5 microM), significantly higher than subcutaneous levels (approx. 30 nM).
- Treatment with adenosine deaminase confirmed adenosine presence.
- Inhibiting adenosine metabolism increased tumor extracellular adenosine to up to 13 microM.
Conclusions:
- Solid tumors contain sufficient extracellular adenosine to suppress local anti-tumor immune responses.
- Targeting adenosine metabolism pathways can markedly increase tumor extracellular adenosine concentrations.
- These findings suggest a potential therapeutic strategy for enhancing anti-tumor immunity by modulating tumor adenosine levels.