Related Experiment Videos
On down-regulation of the immune response to metastatic malignant melanoma
A Håkansson1, B Gustafsson, L Krysander
1Department of Oncology, University Hospital, Linköping, Sweden. annika.hakansson@lio.se
Abstract:
Treatment of metastatic malignant melanoma with interferon alpha (IFNalpha) results in objective remission in approximately 15% of patients. In a previous investigation, we found that about 50% of the patients achieved at least minor or short-lived remissions. In some tumours extensive areas of regressive tumour change occurred. However, even in these areas remnants of tumour cells were generally found. The short duration of the immune response in some patients and the incomplete eradication of the tumour can be due either to selection of non-immunogenic tumour cells or to down-regulation of the immune reactivity to the tumour. In the present paper, the expression of the zeta chain of the T cell receptor in CD3+ lymphocytes and the expression of CD28 in CD3+, CD4+ and CD8+ lymphocytes was studied in resectable melanoma metastases from 20 treated (IFNalpha or IFNalpha in combination with cisplatinum and dacarbazine) and 16 untreated patients. A double-staining technique was used, and the occurrence and distribution of lymphocytes showing down-regulation of the zeta chain or CD28 were separately registered in different areas of the metastases: close to the tumour cells in areas of unaffected tumour growth, in areas with regressive tumour changes, in areas with marked fibrosis and in stromal areas with densely packed lymphocytes. CD3+ zeta lymphocytes were found in all metastases, but their number and distribution varied considerably. Down-regulation of the zeta chain was most often found in areas of regressive changes. In contrast, T lymphocytes infiltrating close to the tumour cells had a stronger expression of the zeta chain (P = 0.016). Down-regulation was also found in stromal areas of densely packed lymphocytes and in areas of fibrosis. The pattern of down-regulation of CD28 in various subsets of lymphocytes was similar to that of zeta chain. The same pattern of down-regulation of CD28 and the zeta chain was found in both untreated and treated patients, indicating that the down-regulation is not due to treatment but to the release of immunosuppressor factors from areas with high tumour cell density or extensive destruction of tumour cells. These results concur well with the view that IFNalpha treatment can result in immune-mediated tumour cell destruction early in the treatment period and that this immune response to the tumour can be followed by immunosuppression within a few weeks.
Insights
Interferon alpha (IFNalpha) treatment for melanoma can lead to immune responses and tumor destruction. However, immunosuppression, indicated by down-regulated T cell receptor zeta chain and CD28 expression, occurs regardless of treatment, suggesting tumor-derived factors are involved.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Metastatic malignant melanoma treatment with interferon alpha (IFNalpha) yields objective remission in ~15% of patients.
- Previous studies showed minor or short-lived remissions in ~50% of patients, with incomplete tumor eradication.
- Incomplete tumor eradication may stem from non-immunogenic tumor cell selection or suppressed immune reactivity.
Purpose of the Study:
- To investigate the expression of T cell receptor zeta chain and CD28 in lymphocytes within melanoma metastases.
- To compare immune marker expression in treated and untreated patients to understand treatment effects and natural disease progression.
- To identify factors contributing to the short duration of immune response and incomplete tumor eradication in melanoma.
Main Methods:
- Studied T cell receptor zeta chain expression in CD3+ lymphocytes and CD28 expression in CD3+, CD4+, and CD8+ lymphocytes.
- Analyzed resectable melanoma metastases from 20 treated (IFNalpha or combination therapy) and 16 untreated patients.
- Employed a double-staining technique to register lymphocyte expression patterns in various metastatic areas (tumor growth, regressive changes, fibrosis, stroma).
Main Results:
- Down-regulation of zeta chain and CD28 was observed in lymphocytes within melanoma metastases.
- Zeta chain down-regulation was most frequent in areas of regressive tumor changes and stromal fibrosis, while T cells near tumor cells showed stronger zeta chain expression.
- Similar patterns of zeta chain and CD28 down-regulation were found in both treated and untreated patients, suggesting it's not treatment-induced but related to tumor microenvironment factors.
Conclusions:
- The observed down-regulation of T cell immune markers is likely due to immunosuppressor factors released from the tumor microenvironment, not IFNalpha treatment itself.
- IFNalpha treatment may initially induce immune-mediated tumor cell destruction.
- This initial immune response can be followed by immunosuppression within weeks, potentially due to tumor cell density or destruction-induced factors.