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Characterization of a tumor necrosis factor-alpha inhibitor activity in cancer patients
N Martinet1, T Charles, P Vaillant
1INSERM Unité 14, Vandoeuvre-les-Nancy, France.
Abstract:
To evaluate the feasibility of tumor necrosis factor-alpha (TNF-alpha) treatment of lung cancer patients, we chose the malignant cells contained in their pleural effusions as a first convenient target. We found, however, that a TNF-alpha inhibitor (TNF-alpha I) activity was present in both patient sera and pleural fluids. We therefore compared the TNF-alpha I activity present in patients with benign or malignant pleural effusions using a bioassay of TNF-alpha inhibition and partially characterized it. A high TNF-alpha I activity characterizes cancer patients with sera levels twice as high as the control level measured for blood bank donors (2.54 +/- 1.28 versus 1.19 +/- 0.38) and with even higher levels in pleural fluids (3.75 +/- 1.83). In contrast, patients with benign pleural effusions present similar levels of TNF-alpha I activity, at about the control level, in both their sera and pleural fluids (1.37 +/- 0.98 versus 1.16 +/- 0.85). A high TNF-alpha I activity is consistently found in cancer patients but is only released in vitro by leukocytes. It is most likely related to recently purified TNF-alpha inhibitors that, as soluble shed fragments of TNF receptors, may function as traps for TNF molecules. This study suggests that tumors may evade TNF cytotoxic action by modulating systemic levels of TNF and implies a reassessment of TNF therapy in cancer patients.
Insights
Cancer patients exhibit elevated tumor necrosis factor-alpha (TNF-alpha) inhibitor activity in blood and pleural fluid. This suggests tumors may evade TNF-alpha
Area of Science:
- Oncology
- Immunology
Background:
- Lung cancer patients were evaluated for tumor necrosis factor-alpha (TNF-alpha) treatment feasibility.
- Malignant cells in pleural effusions were targeted, revealing unexpected TNF-alpha inhibitor (TNF-alpha I) activity.
Purpose of the Study:
- To compare TNF-alpha I activity in patients with benign versus malignant pleural effusions.
- To investigate the source and nature of TNF-alpha I activity in cancer patients.
Main Methods:
- A bioassay was used to measure TNF-alpha inhibition in patient sera and pleural fluids.
- TNF-alpha I activity levels were compared between cancer patients, benign effusion patients, and blood bank donors.
- Partial characterization of the TNF-alpha I activity was performed.
Main Results:
- Cancer patients showed significantly higher TNF-alpha I activity in sera (2.54 +/- 1.28) and pleural fluids (3.75 +/- 1.83) compared to controls (1.19 +/- 0.38).
- Patients with benign pleural effusions had normal TNF-alpha I activity levels, similar to controls.
- High TNF-alpha I activity was consistently found in cancer patients and released in vitro by leukocytes.
Conclusions:
- Elevated TNF-alpha I activity in cancer patients suggests a mechanism for tumors to evade TNF-alpha's cytotoxic effects.
- The inhibitors are likely soluble TNF receptor fragments acting as TNF traps.
- Reassessment of TNF-alpha therapy in cancer patients is implied due to these findings.