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Frequent downregulation of Fas (CD95) expression and function in melanoma
R R Bullani1, P Wehrli, I Viard-Leveugle
1Department of Dermatology, Geneva University Medical School, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland.
Abstract:
Membrane-bound Fas ligand (FasL, Apo-1L, CD95L) induces rapid apoptosis of Fas (CD95)-sensitive cells on interaction with Fas, and is an important effector molecule of cytolytic T lymphocytes (CTLs). Melanomas are immunogenic and induce the production of specific CTLs, but are usually able to escape immune destruction. We investigated Fas expression and function in 53 cutaneous melanocytic lesions and 13 melanoma cell lines grown in vitro. Immunohistochemical analysis of Fas expression in cutaneous melanocytic lesions showed moderate to high levels of Fas in common benign melanocytic naevi, but low to undetectable levels in atypical naevi, primary (superficial spreading melanoma, nodular melanoma) and cutaneous melanoma metastases. Fluorescence-activated cell sorting (FACS) analysis of Fas expression in melanoma cell lines revealed undetectable or low levels of cell surface Fas expression in five of the 13 melanoma cell lines. Analysis of Fas signalling by quantification of cell death following exposure to recombinant FasL showed that a reduction in Fas expression results in resistance to FasL-mediated cell death. Furthermore, two of the 13 melanoma cell lines were found to be resistant to FasL-mediated cell death despite conserved Fas expression. Thus seven of the 13 melanoma cell lines were found to have impaired Fas signalling. Taken together, our results indicate that downregulation of Fas expression and resistance to Fas-mediated apoptosis are frequent in melanoma.
Insights
Melanoma cells often evade immune attack by downregulating Fas receptor expression. This resistance to Fas ligand-mediated apoptosis, crucial for immune cell function, is a common mechanism in melanoma progression.
Area of Science:
- Immunology
- Dermatology
- Molecular Biology
Background:
- Membrane-bound Fas ligand (FasL) induces apoptosis in Fas-sensitive cells, acting as a key effector molecule for cytotoxic T lymphocytes (CTLs).
- Melanomas, despite being immunogenic, frequently escape immune destruction by CTLs.
Purpose of the Study:
- To investigate the expression and function of Fas in various cutaneous melanocytic lesions and melanoma cell lines.
- To determine the role of Fas downregulation and impaired signaling in melanoma's immune evasion.
Main Methods:
- Immunohistochemical analysis of Fas expression in 53 cutaneous melanocytic lesions.
- Fluorescence-activated cell sorting (FACS) analysis of Fas expression in 13 melanoma cell lines.
- Assessment of Fas signaling by quantifying cell death after exposure to recombinant FasL.
Main Results:
- Fas expression was high in benign nevi but low or undetectable in atypical nevi, primary melanomas, and metastases.
- Melanoma cell lines showed reduced or absent surface Fas expression, correlating with resistance to FasL-induced cell death.
- Seven out of 13 melanoma cell lines exhibited impaired Fas signaling, with some resistant to FasL despite conserved Fas expression.
Conclusions:
- Downregulation of Fas expression is a frequent event in melanoma development and progression.
- Melanoma cells frequently develop resistance to Fas-mediated apoptosis, contributing to immune evasion.
- Impaired Fas signaling represents a significant mechanism by which melanomas escape CTL-mediated destruction.