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Inhibition of neutrophil-mediated cytotoxicity by exogenous adenosine 5'-triphosphate
Abstract:
Human polymorphonuclear leukocytes (PMNs) obtained from normal donors kill human tumor cells in vitro. However, if adenosine 5'-triphosphate (ATP) is added to the neutrophil tumor cell suspensions in micromolar concentrations (10-100 microM), there is marked inhibition of neutrophil-mediated cytotoxicity. The inhibitory activity resulted from an effect of ATP on both the effector cells as well as the target cells. When either the effector cells or target cells were preincubated with ATP they became resistant to the effects of the cytotoxic neutrophils. In addition, inhibitory activity was specific to ATP; as it was not demonstrated with GTP, UTP, or CTP. However, when the other adenosine compounds (AMP and ADP) were tested, both AMP and ADP had some inhibitory activity. Cytotoxicity was also inhibited when 100 microM of ATP were added to the neutrophil monolayers either at the time of addition of the tumor cells or 15-60 min after addition of the tumor cells whereas no inhibition of cytotoxicity occurred when ATP was added more than 1 hr after the initiation of the cytotoxic reaction.
Insights
Adenosine triphosphate (ATP) inhibits the ability of human polymorphonuclear leukocytes (PMNs) to kill tumor cells. This immune suppression occurs when ATP affects either the immune cells or the tumor cells directly.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Signaling
Background:
- Human polymorphonuclear leukocytes (PMNs) possess cytotoxic capabilities against tumor cells in vitro.
- The interaction between immune cells and cancer cells is a critical area of cancer research.
Purpose of the Study:
- To investigate the effect of adenosine triphosphate (ATP) on neutrophil-mediated tumor cell cytotoxicity.
- To determine the mechanism and specificity of ATP's inhibitory action on immune cell-cancer cell interactions.
Main Methods:
- In vitro co-culture system using human PMNs and human tumor cells.
- Administration of varying concentrations of ATP and related adenosine compounds (AMP, ADP, GTP, UTP, CTP).
- Pre-incubation experiments with effector (PMNs) and target (tumor) cells prior to co-culture.
- Time-course analysis of ATP addition relative to the initiation of the cytotoxic reaction.
Main Results:
- Micromolar concentrations of ATP (10-100 microM) significantly inhibited PMN-mediated cytotoxicity against tumor cells.
- ATP's inhibitory effect was observed when added to either PMNs or tumor cells prior to co-incubation, rendering them resistant.
- The inhibitory activity was specific to ATP, with minimal effects from GTP, UTP, or CTP, although AMP and ADP showed some inhibition.
- ATP addition up to 60 minutes after tumor cell introduction still inhibited cytotoxicity, but addition after 1 hour had no effect.
Conclusions:
- ATP acts as an inhibitor of neutrophil-mediated tumor cell killing, impacting both immune effector and tumor target cells.
- The findings suggest a potential role for extracellular ATP in modulating anti-tumor immune responses.
- Understanding this ATP-mediated suppression could offer insights into novel immunotherapeutic strategies.