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 epider motropic, CD4+/CD45RO+ (helper/memory) T lymphocytes. Loss of CD8+ CTLs wit hin NIF lesions is associated with poor prognosis and disease progression. Because T-lymphocyte apoptosis is controlled mainly through the Fas/Fas lig and (FasL) pathway and tumor cells may escape immune surveillance by expres sing FasL, triggering apoptosis of tumorinfiltrating T lymphocytes, we stud ied the role of this system in NIF. T-cell subsets, Fas/FasL expression, an d apoptosis were evaluated in normal and lesional skin biopsy specimens fro m 21 patients with all stages of MF and in cultured CTCL cell lines (NU, HU T78, and HH) using immunohistochemistry, terminal deoxynucleotidyl transfer ase-mediated dUTP nick end labeling (TUNEL), and Western blotting. NIF lesi ons and paired, clinically "normal," uninvolved skin showed increased numbe rs 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 < 0.0 1, ANOVA) compared with the normal control skin. FasL expression was highes t in lesional epidermal keratinocytes, in CTCL tumor cell lines, and in der mal tumor lymphocytes in MF lesions compared with uninvolved skin. FasL col ocalized with CD45RO+ cells. CD8+ cells in or adjacent to CD45RO+ cells wer e 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 < 0.0 2). These results suggest that a potential mechanism of tumor immune escape in MF is FasL-mediated apoptosis of infiltrating CD8+ CTLs.