Summary Interferon alpha (IFN-a) has a documented activity against malignant melanoma with a response rate of only approximately 20%. It would therefore be of considerable importance if patients likely to respond could be identified. The degree of mononuclear cell infiltration in primary tumours has been reported to correlate with a favourable prognosis. This investigation used monoclonal antibodies, anti-CD4, -CD8 and -CD 1 lc, to identify subsets of tumour-infiltrating mononuclear cells in fine needle aspirates to study whether the presence of such cells correlates with the therapeutic effect of IFN-a. Twenty-one patients with systemic and 20 with regional metastatic malignant melanoma were studied before initiation of IFN-a treatment. A statistically significant correlation (P<0.001) was found between the occurrence of CD4+ lymphocytes in fine needle aspirates and the therapeutic benefit of IFN-a in patients with systemic disease. Ten out of 11 with moderate to high numbers of infiltrating CD4+ lymphocytes achieved tumour regression. In contrast, among patients with low numbers of these cells in metastatic lesions, nine out of ten had progressive disease. Similar results were found in patients with regional disease.

A large number of studies have indicated that specific immune reactivity plays a crucial role in the control of malignant melanoma. In this context, expression of MHC I, MHC II and B7 molecules by melanoma cells is seen as relevant for the immune response against the tumour. For a better understanding of the biological relevance of MHC II and B7 expression by tumour cells in metastatic melanoma, we studied the expression of these molecules in melanoma metastases in relation to the inflammatory response, regression of the tumour and survival from 27 patients treated with biochemotherapy (30 mg m À2 Cisplatin and 250 mg m À2 decarbazine (dimethyl-triazene-imidazole-carboxamide, DTIC) on days 1 -3 i.v., and 10 7 IU IFN-a2b 3 days a week s.c., q. 28d). In 19 out of 27 lesions studied, we found expression of MHC II by the tumour cells, while only in one out of 11 tumour biopsies obtained from untreated metastatic melanoma patients, MHC II expression was detected.

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Interferon-alpha (INF-alpha) has a documented activity against metastatic melanoma. To what extent an antiproliferative effect or tumor cell modulation or immunomodulation contributes to this antitumor effect is still uncertain. The role of immune mechanisms in the control of malignant melanoma is suggested by several studies. Therefore, this investigation used monoclonal antibodies, anti-CD4, anti-CD8, and anti-CD11c, to study the occurrence and distribution of tumor-infiltrating mononuclear cells in 10 untreated and 26 IFN-alpha-treated patients with regional metastatic malignant melanoma. IFN-alpha was given for 1-3 weeks before resection of the metastases. The infiltration of mononuclear cells in the stroma and close to tumor cells was studied. The duration of IFN-alpha treatment was found to be of importance for the immunomodulatory effect. In patients treated for < or = 1 week, tumor-infiltrating mononuclear cells were still mainly localized in the stroma, similar to the situation in untreated patients. The differences in CD4+ cells close to the tumor cells, comparing untreated patients and patients with various durations of IFN-alpha treatment, were highly significant (p = 0.009). Thus, IFN-alpha treatment resulted in recruitment of CD4+ cells close to the tumor cells. IFN-alpha had only a weak effect on the recruitment of CD8+ and CD11c+ mononuclear cells close to the tumor cells. Regressive changes in metastases were also analyzed and correlated to duration of treatment. Some of the criteria used for histopathologic regression in primary melanoma (distorted histologic architecture, low tumor cell density, and fibrosis) were applied to analyze the effect of IFN-alpha in metastatic melanoma. The tumor cell density was found to be significantly reduced in metastases with marked tumor regression compared with metastases with no, or only minor, regressive changes (p < 0.005). A chi-square analysis for trend, comparing untreated patients and patients with various durations of IFN-alpha treatment, showed that regressive changes of the tumor increased significantly during IFN-alpha treatment (p = 0.02).

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