Submitted August 23, 2007
Accepted January 15, 2008
Resistance to FasL and TRAIL-mediated apoptosis in Sezary syndrome T-cells associated with impaired death receptor and cFLIP expression
Emmanuel Contassot, Katrin Kerl, Stephanie Roques, Ryan Shane, Olivier Gaide, Marc Dupuis, Alain H Rook, and Lars E French*
Department of Dermatology, Zurich University Hospital, Zurich, Switzerland
Department of Pathology and Immunology, Louis-Jeantet Skin Cancer Laboratory, University Medical Center, Geneva, Switzerland
Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Department of Dermatology, Geneva University Hospital, Geneva, Switzerland
Topotarget Switzerland, Lausanne, Switzerland
* Corresponding author; email: lars.french{at}usz.ch.
Due to the low proliferative potential of tumor cells in Sezary's Syndrome (SzS) patients, their accumulation has been suggested to be due to defective regulation of apoptosis. We analyzed the sensitivity to soluble Fas-ligand (FasL) and TRAIL, two members of the TNF-superfamily in SzS patients PBL. In comparison to healthy donors, CD4+ cells from SzS patients were completely resistant to FasL in 9/16 cases. Of these 9 FasL-resistant cases, 4 revealed a loss in Fas (CD95) expression, whereas the remaining 5 exhibited normal or enhanced Fas expression. In the latter 5 cases, the apoptosis inhibitor cFLIP was overexpressed in CD4+/CD26- tumor cells when compared to CD4+/CD26- cells from Fas-expressing FasL-sensitive patients and healthy donors. Furthermore, resistance to TRAIL and tumor cell-restricted loss of TRAIL-receptor 2 were observed in 16/16 SzS PBL. Interestingly, resistance to FasL could be overcome by the use of an hexameric FasL or upon exposure of SzS cells to IFN-
or -
, the latter by an increase of Fas expression. Our data on primary SzS lymphocytes reveal frequent resistance to apoptosis induced by FasL and TRAIL which may contribute to their accumulation in SzS patients and be relevant at a therapeutic level.
