Interferon-alpha based treatment of metastatic malignant melanoma : Effect of immune parameters of importance for monitoring immunotherapy

Sammanfattning: Cutaneous malignant melanoma is a rapidly increasing disease. Most patients are cured by surgical excision of their primary tumour, but for patients with metastatic disease the prognosis is still very poor despite various attempts with chemotherapeutic agents, and during the last decade with immunotherapy, using several different biological agents alone or in combination. Thus, there is a great need for a better understanding of various functions of the immune system, tools for monitoring immunotherapy and predictive tests for choosing patients who are suitable for this therapy.The aims of the present investigation was therefore to study factors of possible importance for the immune control of tumours such as the occurrence and distribution of tumour-infiltrating mononuclear cells, expression ofTNFa, ICAM-1 and down-regulation of the function of tumour-infiltrating mononuclear cells. Using fine-needle aspiration of melanoma metastases we show a correlation between the occurrence of CD4+ lymphocytes in the metastases and the therapeutic benefit ofiFN-a. Thus, the degree of infiltration of these cells seems to be a useful predictive test for choosing patients suited to this therapy. We report that the expression of ICAM-1 on tumour cells is up-regulated after IFN-a treatment and describe a correlation between the expression of ICAM-1 by tumour cells and infiltration of CD4+ lymphocytes in the metastases. Thus, deternllning of ICAM:- 1 expression by tumour cells obtained by fine needle aspiration could perhaps be a valuable supplement to detennining the occurrence of tumour-infiltrating CD4+ lymphocytes tocorrelate with the response to IFN-a treatment.We demonstrate a low immune reactivity in melanoma metastases with a high expression of TNF-a by the tumour cells in untreated metastases and that IFN-a treatment could increase the immune reactivity. We also demonstrate that during the second week ofiFN-a treatment tumour-infiltrating CD4+ lymphocytes migrate from the stromal areas into the tumour nodules, close to the tumour cells, and that the extent of the tumour areas with regressive changes was significantly enhanced compared to untreated patients. Markers of the function of tumour infiltrating lymphocytes, the ~-chain and CD28, were found to be down-regulated, especially in areas of extensive tumour regression. Taken together our results are compatible with the view that the immunostimulating effect of IFNa, resulting in immune-mediated tumour cell destruction, occurs early during the treatment period and is followed within a few weeks by down-regulation of the anti-tumour immune response. Thus, in immunotherapy the possibility of inducing immunosuppression due to the lysis of tumour cells and the release of immunosuppressor factors should be considered and monitored.