Autocrine secretion of Fas ligand shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes.

Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Cancer Research (Impact Factor: 9.28). 10/2004; 64(18):6775-82. DOI: 10.1158/0008-5472.CAN-04-0508
Source: PubMed

ABSTRACT Mechanisms responsible for resistance of tumors to death receptor-mediated damage by cytotoxic lymphocytes are not well understood. Uveal melanoma cells expressed Fas but were insensitive to Fas triggering induced by bystander cytotoxic T lymphocytes or a Fas-specific agonistic antibody; this could not be ascribed to tumor counterattack against T cells or general resistance of the tumors to apoptosis. Treatment with inhibitors of metalloproteases rendered uveal melanomas sensitive to Fas-mediated cytotoxicity. Metalloprotease inhibitors did not affect the expression of Fas but increased the surface expression of Fas ligand (FasL), which correlated with the disappearance of soluble FasL from culture supernatants of tumor cells. FasL eluted from the surface of uveal melanomas specifically inhibited cytotoxic T lymphocyte lysis of tumor cells pretreated with an inhibitor of metalloproteases. In addition to uveal melanomas, a number of other tumor cell lines of various cellular origins were sensitized to Fas-mediated cytotoxicity by metalloprotease inhibitors. Our results show that autocrine secretion of FasL shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes. This defines a novel mechanism of tumor escape from immune surveillance.

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Available from: Victor Levitsky, Jun 20, 2014
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    • "Multiple studies have shown melanoma tumors express detectable surface FasL expression both in vivo and in vitro and that this ligand may act as a first line immunosuppressor through inhibiting CTL activity (Shukuwa et al., 2002; Andreola et al., 2002). High surface FasL expression also correlates with poor disease prognosis, but whether this is due to enhanced immune impairment or through an autocrine tolerization against FasL-FasR binding remains unknown (Hallermalm et al., 2004). Fig. 3. Costimulatory Signals in Melanoma. "
    Treatment of Metastatic Melanoma, 10/2011; , ISBN: 978-953-307-574-7
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    • "Alternatively , secretion of processed " soluble " FasL [6] or FasLbearing microvesicles [7] by cancer cells may create a specific shield, which allows them to dampen the effects of cytotoxic lymphocytes or natural killer cells. A role of endogenous FasL expression in the " tumor counterattack " hypothesis is still under active investigation [3] [8] [9]; however , experimental data certainly demonstrated FasL expression in some cancer cell lines, including melanomas [6] [7] [10] [11]. Taken together, these observations illustrate important aspects of the general problem of the resistance of cancer cells to the induction of programmed cell death. "
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    ABSTRACT: Most human melanomas express Fas receptor on the cell surface, and treatment with exogenous Fas Ligand (FasL) efficiently induces apoptosis of these cells. In contrast, endogenous surface expression of FasL is suppressed in Fas-positive melanomas. We report here the use of a combination of sodium arsenite, an inhibitor of NF-kappaB activation, and NS398, a cyclooxygenase-2 (COX-2) inhibitor, for restoration of the surface FasL expression. We observed a large increase of Fas-mediated apoptosis in Fas-positive melanomas. This was due to induction of FasL surface expression and increased susceptibility to Fas death signaling after arsenite and NS398 treatment. Furthermore, silencing COX-2 expression by specific RNAi also effectively increased surface FasL expression following arsenite treatment. Upregulation of the surface FasL levels was based on an increase in the efficiency of translocation to the cell surface and stabilization of FasL protein on the cell surface, rather than on acceleration of the FasL gene transcription. Data obtained demonstrate that the combination of arsenite with inhibitors of COX-2 may affect the target cancer cells via induction of FasL-mediated death signaling.
    Experimental Cell Research 06/2006; 312(8):1401-17. DOI:10.1016/j.yexcr.2006.01.003 · 3.37 Impact Factor
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