EFFECT OF IFN-ALPHA ON TUMOR-INFILTRATING MONONUCLEAR-CELLS AND REGRESSIVE CHANGES IN METASTATIC MALIGNANT-MELANOMA

Interferon-alpha (INF-alpha) has a documented activity against metasti c melanoma. To what extent an antiproliferative effect or tumor cell m odulation or immunomodulation contributes to this antitumor effect is still uncertain. The role of immune mechanisms in the control of malig nant melanoma is suggested by several studies. Therefore, this investi gation used monoclonal antibodies, anti-CD4 anti-CD8, and anti-CD11c, to study the occurrence and distribution of tumor-infiltrating mononuc lear cells in 10 untreated and 26 IFN-alpha-treated patients with regi onal metastatic malignant melanoma. IFN-alpha was given for 1-3 weeks before resection of the metastases. The infiltration of mononuclear ce lls in the stroma and close to tumor cells was studied. The duration o f IFN-alpha treatment was found to be of importance for the immunomodu latory effect. In patients treated for less than or equal to 1 week, t umor-infiltrating mononuclear cells were still mainly localized in the stroma, similar to the situation in untreated patients. The differenc es in CD4(+) cells close to the tumor cells, comparing untreated patie nts and patients with various durations of IFN-alpha treatment, were h ighly significant (p = 0.009). Thus, IFN-alpha treatment resulted in r ecruitment of CD4(+) cells close to the tumor cells. IFN-alpha had onl y 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 cri teria used for histopathologic regression in primary melanoma (distort ed histologic architecture, low tumor cell density, and fibrosis) were applied to analyze the effect of IFN-alpha in metastatic melanoma. Th e tumor cell density was found to be significantly reduced in metastas es with marked tumor regression compared with metastases with no, or o nly minor, regressive changes (p < 0.005). A chi-square analysis for t rend, comparing untreated patients and patients with various durations of IFN-alpha treatment, showed that regressive changes of the tumor i ncreased significantly during IFN-alpha treatment (p = 0.02).