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Alterations in T cell receptor and signal transduction molecules in melanoma patients
Abstract:
We have recently described molecular changes in T cells from tumor-bearing patients that are associated with depressed immune function. The present work investigates changes in T-cell signal transduction proteins including the T-cell receptor-zeta (TCR-zeta) chain and receptor-associated tyrosine kinases in patients with metastatic malignant melanoma. A marked decrease in the expression of the TCR-zeta chain was observed in the peripheral blood T cells of 19 (43%) of 44 patients. Decreases in several tyrosine kinases were found in 12 (57%) of 21 patients tested. T cells from patients with diminished TCR-zeta chain expression also showed statistically significant differences in cytokine production pattern, with lower interleukin 2 and IFN-zeta production compared with normal subjects and melanoma patients with normal TCR-zeta chain status. The overall survival of melanoma patients with low TCR-zeta chain expression was significantly shorter than that of patients with normal TCR-zeta chain expression (P = 0.0013). TCR-zeta-deficient patients showed a trend toward having faster growing tumors. There was no correlation between the pretreatment TCR-zeta chain status and albumin or performance status. These findings suggest that alterations in T-cell function occur commonly in melanoma patients and may be independent predictors of clinical outcome.
Insights
Molecular changes in T cells, including decreased T-cell receptor-zeta (TCR-zeta) chain expression, are common in melanoma patients. This immune dysfunction is linked to poorer survival and faster tumor growth, suggesting TCR-zeta as a potential prognostic marker.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- T cells play a crucial role in anti-tumor immunity.
- Molecular alterations in T cells can lead to immune dysfunction in cancer patients.
- Previous work identified T-cell molecular changes associated with depressed immune function in tumor-bearing individuals.
Purpose of the Study:
- To investigate alterations in T-cell signal transduction proteins, specifically the T-cell receptor-zeta (TCR-zeta) chain and associated tyrosine kinases.
- To examine the relationship between TCR-zeta chain expression and clinical outcomes in metastatic malignant melanoma patients.
Main Methods:
- Analysis of T-cell receptor-zeta (TCR-zeta) chain expression in peripheral blood T cells from melanoma patients.
- Assessment of receptor-associated tyrosine kinase levels.
- Evaluation of cytokine production patterns (Interleukin-2, IFN-zeta).
- Correlation analysis with overall survival, tumor growth, albumin, and performance status.
Main Results:
- A significant decrease in TCR-zeta chain expression was observed in 43% of melanoma patients.
- Reduced expression of tyrosine kinases was found in 57% of patients tested.
- T cells with diminished TCR-zeta showed lower Interleukin-2 and IFN-zeta production.
- Low TCR-zeta expression was significantly associated with shorter overall survival (P=0.0013) and a trend towards faster tumor growth.
Conclusions:
- Alterations in T-cell function, particularly decreased TCR-zeta chain expression, are prevalent in melanoma patients.
- TCR-zeta chain status appears to be an independent predictor of clinical outcome in melanoma.
- These molecular changes may contribute to immune evasion and disease progression in melanoma.