Fas ligand expression by neoplastic T lymphocytes mediates elimination of CD8+ cytotoxic T lymphocytes in mycosis fungoides : A potential mechanism of tumor immune escape?

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and arises from the accumulation and clonal proliferation of epidermotropic, CD4+/CD45RO+ (helper/memory) T lymphocytes. Loss of CD8+ CTLs within MF lesions is associated with poor prognosis and disease progression. B...

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Veröffentlicht in:Clinical cancer research 2001-09, Vol.7 (9), p.2682-2692
Hauptverfasser: XIAO NI, HAZARIKA, Parul, CHUNLEI ZHANG, TALPUR, Rakhashandra, DUVIC, Madeleine
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creator XIAO NI
HAZARIKA, Parul
CHUNLEI ZHANG
TALPUR, Rakhashandra
DUVIC, Madeleine
description Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and arises from the accumulation and clonal proliferation of epidermotropic, CD4+/CD45RO+ (helper/memory) T lymphocytes. Loss of CD8+ CTLs within MF lesions is associated with poor prognosis and disease progression. Because T-lymphocyte apoptosis is controlled mainly through the Fas/Fas ligand (FasL) pathway and tumor cells may escape immune surveillance by expressing FasL, triggering apoptosis of tumor-infiltrating T lymphocytes, we studied the role of this system in MF. T-cell subsets, Fas/FasL expression, and apoptosis were evaluated in normal and lesional skin biopsy specimens from 21 patients with all stages of MF and in cultured CTCL cell lines (MJ, HUT78, and HH) using immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and Western blotting. MF lesions and paired, clinically "normal," uninvolved skin showed increased numbers of both TUNEL-positive epidermal keratinocytes (n = 13; F = 31.146; P < 0.01, ANOVA) and dermal lymphocyte infiltrates (n = 13; F = 15.825, P < 0.01, ANOVA) compared with the normal control skin. FasL expression was highest in lesional epidermal keratinocytes, in CTCL tumor cell lines, and in dermal tumor lymphocytes in MF lesions compared with uninvolved skin. FasL colocalized with CD45RO+ cells. CD8+ cells in or adjacent to CD45RO+ cells were positively labeled by TUNEL for apoptosis. In addition, CD8+ cell numbers were decreased in areas in which FasL+ tumor cells were abundant (2.01 +/- 0.86%) compared with non-FasL expressing areas (13.53 +/- 3.54%; P < 0.02). These results suggest that a potential mechanism of tumor immune escape in MF is FasL-mediated apoptosis of infiltrating CD8+ CTLs.
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Loss of CD8+ CTLs within MF lesions is associated with poor prognosis and disease progression. Because T-lymphocyte apoptosis is controlled mainly through the Fas/Fas ligand (FasL) pathway and tumor cells may escape immune surveillance by expressing FasL, triggering apoptosis of tumor-infiltrating T lymphocytes, we studied the role of this system in MF. T-cell subsets, Fas/FasL expression, and apoptosis were evaluated in normal and lesional skin biopsy specimens from 21 patients with all stages of MF and in cultured CTCL cell lines (MJ, HUT78, and HH) using immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and Western blotting. MF lesions and paired, clinically "normal," uninvolved skin showed increased numbers of both TUNEL-positive epidermal keratinocytes (n = 13; F = 31.146; P &lt; 0.01, ANOVA) and dermal lymphocyte infiltrates (n = 13; F = 15.825, P &lt; 0.01, ANOVA) compared with the normal control skin. FasL expression was highest in lesional epidermal keratinocytes, in CTCL tumor cell lines, and in dermal tumor lymphocytes in MF lesions compared with uninvolved skin. FasL colocalized with CD45RO+ cells. CD8+ cells in or adjacent to CD45RO+ cells were positively labeled by TUNEL for apoptosis. In addition, CD8+ cell numbers were decreased in areas in which FasL+ tumor cells were abundant (2.01 +/- 0.86%) compared with non-FasL expressing areas (13.53 +/- 3.54%; P &lt; 0.02). 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FasL expression was highest in lesional epidermal keratinocytes, in CTCL tumor cell lines, and in dermal tumor lymphocytes in MF lesions compared with uninvolved skin. FasL colocalized with CD45RO+ cells. CD8+ cells in or adjacent to CD45RO+ cells were positively labeled by TUNEL for apoptosis. In addition, CD8+ cell numbers were decreased in areas in which FasL+ tumor cells were abundant (2.01 +/- 0.86%) compared with non-FasL expressing areas (13.53 +/- 3.54%; P &lt; 0.02). 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Loss of CD8+ CTLs within MF lesions is associated with poor prognosis and disease progression. Because T-lymphocyte apoptosis is controlled mainly through the Fas/Fas ligand (FasL) pathway and tumor cells may escape immune surveillance by expressing FasL, triggering apoptosis of tumor-infiltrating T lymphocytes, we studied the role of this system in MF. T-cell subsets, Fas/FasL expression, and apoptosis were evaluated in normal and lesional skin biopsy specimens from 21 patients with all stages of MF and in cultured CTCL cell lines (MJ, HUT78, and HH) using immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and Western blotting. MF lesions and paired, clinically "normal," uninvolved skin showed increased numbers of both TUNEL-positive epidermal keratinocytes (n = 13; F = 31.146; P &lt; 0.01, ANOVA) and dermal lymphocyte infiltrates (n = 13; F = 15.825, P &lt; 0.01, ANOVA) compared with the normal control skin. FasL expression was highest in lesional epidermal keratinocytes, in CTCL tumor cell lines, and in dermal tumor lymphocytes in MF lesions compared with uninvolved skin. FasL colocalized with CD45RO+ cells. CD8+ cells in or adjacent to CD45RO+ cells were positively labeled by TUNEL for apoptosis. In addition, CD8+ cell numbers were decreased in areas in which FasL+ tumor cells were abundant (2.01 +/- 0.86%) compared with non-FasL expressing areas (13.53 +/- 3.54%; P &lt; 0.02). These results suggest that a potential mechanism of tumor immune escape in MF is FasL-mediated apoptosis of infiltrating CD8+ CTLs.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>11555580</pmid><tpages>11</tpages></addata></record>
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ispartof Clinical cancer research, 2001-09, Vol.7 (9), p.2682-2692
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source MEDLINE; American Association for Cancer Research; Alma/SFX Local Collection; EZB Electronic Journals Library
subjects Adult
Aged
Apoptosis
Biological and medical sciences
CD8 Antigens - metabolism
Fas Ligand Protein
Female
General aspects (metabolism, cell proliferation, established cell line...)
Humans
Immunohistochemistry
In Situ Nick-End Labeling
Jurkat Cells
Leukocyte Common Antigens - metabolism
Male
Medical sciences
Membrane Glycoproteins - biosynthesis
Middle Aged
Mycosis Fungoides - immunology
Mycosis Fungoides - metabolism
Mycosis Fungoides - pathology
Skin - chemistry
Skin - immunology
Skin - pathology
Skin Neoplasms - immunology
Skin Neoplasms - metabolism
Skin Neoplasms - pathology
T-Lymphocytes - chemistry
T-Lymphocytes - immunology
T-Lymphocytes - pathology
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Cytotoxic - metabolism
T-Lymphocytes, Cytotoxic - pathology
Tumor cell
Tumor Cells, Cultured
Tumors
title Fas ligand expression by neoplastic T lymphocytes mediates elimination of CD8+ cytotoxic T lymphocytes in mycosis fungoides : A potential mechanism of tumor immune escape?
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