Effect of interferon-α on the expression of tumour necrosis factor-α by metastatic malignant melanoma in vivo

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Abstract
To our knowledge modulation of the expression of tumour necrosis factor-alpha (TNF-alpha) in malignant melanoma metastases in vivo has not been reported. The expression of TNF-alpha by malignant melanoma cells was studied immunohistochemically using an anti-TNF-alpha antibody. The specificity of the staining reaction was demonstrated by absorption of the TNF-alpha antibody with human recombinant TNF-alpha, which inhibited the staining reaction. The TNF-alpha expression was also verified by in situ hybridization for mRNA. Metastases from 37 patients were studied, 21 of whom were treated with IFN-alpha. All 16 metastases from untreated patients were positive for TNF-alpha. Based on the average staining intensity of the melanoma cells for TNF-alpha, the metastases were classified into two groups. The expression of TNF-alpha varied considerably between metastases from different patients and also within the same metastasis. Melanoma cells in areas with low cellularity and large numbers of infiltrating inflammatory cells were generally weakly stained. This is in good agreement with a low staining score for TNF-alpha in metastases showing marked histopathological regression. Seven out of 13 patients with a low staining score for TNF-alpha showed a marked regression of their tumours. In contrast one out of five patients with a high staining score for TNF-alpha showed a marked tumour regression, suggesting that tumour cells sensitive to immune-mediated regression express less TNF-alpha. Interferon-alpha (IFN-alpha) appears to modulate the expression of TNF-alpha. Significantly more patients treated with IFN-alpha had metastases with a low TNF-alpha staining score compared with untreated patients. Thus, seven out of 21 patients treated with IFN-alpha showed a high expression of TNF-alpha in contrast to 13 out of 16 in the untreated group (P = 0.01).

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