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: 9.33). 10/2004; 64(18):6775-82. DOI: 10.1158/0008-5472.CAN-04-0508
Source: PubMed


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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    • "The interaction between tumor cells and immune cells during heterotypic cell-in-cell structure formation observed arouses new questions as what the physiological significance is for this phenomenon. It is widely accepted that tumors escape from immune surveillance through several intrinsic mechanisms, including the weak immunogenicity of tumor antigens [12], down-regulation of major histocompatibility complex (MHC) molecules on tumor cells[13]–[14], defects of antigen processing machinery [13], [15] or the release of immuno-suppressive molecules[16]–[17]. With the observation of heterotypic cell-in-cell structures in tumors[18]–[19], it is possible that lymphocytes infiltration into tumor regions facilitates the direct cell-cell contact for the formation of heterotypic cell-in-cell structures described here. "
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    ABSTRACT: Cell-in-cell structures refer to a unique phenomenon that one living cell enters into another living cell intactly, occurring between homotypic tumor cells or tumor (or other tissue cells) and immune cells (named as heterotypic cell-in-cell structure). In the present study, through a large scale of survey we observed that heterotypic cell-in-cell structure formation occurred commonly in vitro with host cells derived from different human carcinomas as well as xenotypic mouse tumor cell lines. Most of the lineages of human immune cells, including T, B, NK cells, monocytes as well as in vitro activated LAK cells, were able to invade tumor cell lines. Poorly differentiated stem cells were capable of internalizing immune cells as well. More significantly, heterotypic tumor/immune cell-in-cell structures were observed in a higher frequency in tumor-derived tissues than those in adjacent tissues. In mouse hepatitis models, heterotypic immune cell/hepatocyte cell-in-cell structures were also formed in a higher frequency than in normal controls. After in vitro culture, different forms of internalized immune cells in heterotypic cell-in-cell structures were observed, with one or multiple immune cells inside host cells undergoing resting, degradation or mitosis. More strikingly, some internalized immune cells penetrated directly into the nucleus of target cells. Multinuclear cells with aneuploid nucleus were formed in target tumor cells after internalizing immune cells as well as in situ tumor regions. Therefore, with the prevalence of heterotypic cell-in-cell structures observed, we suggest that shielding of immune cells inside tumor or inflammatory tissue cells implies the formation of aneuploidy with the increased multinucleation as well as fine-tuning of microenvironment under pathological status, which may define distinct mechanisms to influence the etiology and progress of tumors.
    Full-text · Article · Mar 2013 · PLoS ONE
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    • "By contrast, depending on the cell type and its state, FasL-Fas system has also been shown to be instructive signal for ongoing and injury-induced brain regeneration [10]. Despite the autocrine action of FasL that has been shown in vascular smooth muscle cells [14], epithelial cells [15], lymphocytes [16], and intestinal cells [17], little is known about its effects on microglia or its possible role in brain microembolic injury. Due to the dual and insufficient knowledge about FasL-Fas system in the brain, discrete targets amenable to ischemic processes need to be identified and functionally validated. "
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    ABSTRACT: The cerebral microvascular occlusion elicits microvascular injury which mimics the different degrees of stroke severity observed in patients, but the mechanisms underlying these embolic injuries are far from understood. The Fas ligand (FasL)-Fas system has been implicated in a number of pathogenic states. Here, we examined the contribution of microglia-derived FasL to brain inflammatory injury, with a focus on the potential to suppress the FasL increase by inhibition of the P2X(7)-FasL signaling with pharmacological or genetic approaches during ischemia. The cerebral microvascular occlusion was induced by microsphere injection in experimental animals. Morphological changes in microglial cells were studied immunohistochemically. The biochemical analyses were used to examine the intracellular changes of P2X(7)/FasL signaling. The BV-2 cells and primary microglia from mice genetically deficient in P2X(7) were used to further establish a linkage between microglia activation and FasL overproduction. The FasL expression was continuously elevated and was spatiotemporally related to microglia activation following microsphere embolism. Notably, P2X(7) expression concomitantly increased in microglia and presented a distribution pattern that was similar to that of FasL in ED1-positive cells at pathological process of microsphere embolism. Interestingly, FasL generation in cultured microglia cells subjected to oxygen-glucose deprivation-treated neuron-conditioned medium was prevented by the silencing of P2X(7). Furthermore, FasL induced the migration of BV-2 microglia, whereas the neutralization of FasL with a blocking antibody was highly effective in inhibiting ischemia-induced microglial mobility. Similar results were observed in primary microglia from wild-type mice or mice genetically deficient in P2X(7). Finally, the degrees of FasL overproduction and neuronal death were consistently reduced in P2X(7)(-/-) mice compared with wild-type littermates following microsphere embolism insult. FasL functions as a key component of an immunoreactive response loop by recruiting microglia to the lesion sites through a P2X(7)-dependent mechanism. The specific modulation of P2X(7)/FasL signaling and aberrant microglial activation could provide therapeutic benefits in acute and subacute phase of cerebral microembolic injury.
    Full-text · Article · Jul 2012 · Journal of Neuroinflammation
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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. "

    Full-text · Chapter · Oct 2011
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