Induction of Lymphocyte Apoptosis by Tumor Cell Secretion of FasL-bearing Microvesicles

By G. Andreola, L. Rivoltini, C. Castelli, V. Huber, P. Perego, Paola Deho, P. Squarcina, P. Accornero, F. Lozupone, L. Lugini and 6 more. Journal of Experimental Medicine, 2002

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The hypothesis that FasL expression by tumor cells may impair the in vivo efficacy of antitumor immune responses, through a mechanism known as ‘Fas tumor counterattack,’ has been recently questioned, becoming the object of an intense debate based on conflicting results. Here we definitely show that FasL is indeed detectable in the cytoplasm of melanoma cells and its expression is confined to multivesicular bodies that contain melanosomes. In these structures FasL colocalizes with both melanosomal (i.e., gp100) and lysosomal (i.e., CD63) antigens. Isolated melanosomes express FasL, as detected by Western blot and cytofluorimetry, and they can exert Fas-mediated apoptosis in Jurkat cells. We additionally show that melanosome-containing multivesicular bodies degranulate extracellularly and release FasL-bearing microvesicles, that coexpress both gp100 and CD63 and retain their functional activity in triggering Fas-dependent apoptosis of lymphoid cells. Hence our data provide evidence for a novel mechanism potentially operating in Fas tumor counterattack through the secretion of subcellular particles expressing functional FasL. Such vesicles may form a sort of front line hindering lymphocytes and other immunocompetent cells from entering neoplastic lesions and exert their antitumor activity.

Subfields: Molecular Biology, Parasitology

View Paper: https://www.semanticscholar.org/paper/4536f31c4b96cca3535424dc50f5b56e210d4ecc

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Citations in the corpus

Exosome-Based Cell-Cell Communication in the Tumor Microenvironment (2018, result): “In addition, tumor-derived exosomes containing death receptor ligands, such as FasL, on their membrane were also found to induce the apoptosis of NK cells, similarly to what happens with T cells (Andreola et al., 2002; Saito et al., 2013).”
Exosomes: secreted vesicles and intercellular communications (2011, background): “The information transferred could include antigens or MHC–peptide complexes for increasing the range of antigen-presenting cells and the efficiency of induction of immune responses [13-15], or in some cases negative signals leading to death of the target cell [16].”
Exosome Function: From Tumor Immunology to Pathogen Biology (2008, background): “Moreover, exosomes from T cells, melanoma cells and ovarian tumor cells have been shown to carry FasL, which could induce T-cell apoptosis (59,60).”
Review of the Isolation, Characterization, Biological Function, and Multifarious Therapeutic Approaches of Exosomes (2019, background): “Exosomes derived from cancer cells inhibit cell proliferation, have cytotoxic effects on natural killer (NK) cells, and induce T cell apoptosis by carrying the Fas ligand [153,154].”
Exosomes: composition, biogenesis and function (2002, background): “Finally, melanoma cells also secrete FASL-bearing exosome-like vesicles that have pro-apoptotic activity on T cell”
Exosomes and their roles in immune regulation and cancer. (2015, background): “Andreola and colleagues demonstrated that in melanoma cells, Fas ligand (FasL) was restricted to MVBs that contain melanosomes [118].”
The biology and function of exosomes in cancer. (2016, background): “Fas ligand (FasL) on cancer cell–derived exosomes induces apoptosis of Fas+ T cells (67).”
High Levels of Exosomes Expressing CD63 and Caveolin-1 in Plasma of Melanoma Patients (2009, background): “In particular, we and others have recently shown that exosomes secreted by human tumor cells of various origins are able to induce apoptosis in activated T cells, through the expression of death ligands (e.g. FasL, TRAIL) [9,10,13], inhibit NK functions [14,15] and promote the generation of myeloid-”
Immunosuppressive strategies that are mediated by tumor cells. (2007, background): “N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript In addition, it has been speculated that acquisition of FasL may enable cancer cells to deliver death signals to activated Fas-positive T-lymphocytes (102–105).”
Natural selection of tumor variants in the generation of “tumor escape” phenotypes (2002, background): “The most recent study on this controversial topic asserts that FasL is coexpressed with melanosomal and lysosomal markers in multivesicular bodies in human melanoma cell”