title: Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes.
abstract: Sera of patients with cancer contain membraneous microvesicles (MV) able to induce apoptosis of activated T cells by activating the Fas/Fas ligand pathway. However, the cellular origin of MV found in cancer patients' sera varies as do their molecular and cellular profiles. To distinguish tumor-derived MV in cancer patients' sera, we used MAGE 3/6(+) present in tumors and MV. Molecular profiles of MAGE 3/6(+) MV were compared in Western blots or by flow cytometry with those of MV secreted by dendritic cells or activated T cells. These profiles were found to be distinct for each cell type. Only tumor-derived MV were MAGE 3/6(+) and were variably enriched in 42-kDa Fas ligand and MHC class I but not class II molecules. Effects of MV on signaling via the TCR and IL-2R and proliferation or apoptosis of activated primary T cells and T cell subsets were also assessed. Functions of activated CD8(+) and CD4(+) T lymphocytes were differentially modulated by tumor-derived MV. These MV inhibited signaling and proliferation of activated CD8(+) but not CD4(+) T cells and induced apoptosis of CD8(+) T cells, including tumor-reactive, tetramer(+)CD8(+) T cells as detected by flow cytometry for caspase activation and annexin V binding or by DNA fragmentation. Tumor-derived but not dendritic cell-derived MV induced the in vitro expansion of CD4(+)CD25(+)FOXP3(+) T regulatory cells and enhanced their suppressor activity. The data suggest that tumor-derived MV induce immune suppression by promoting T regulatory cell expansion and the demise of antitumor CD8(+) effector T cells, thus contributing to tumor escape.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Eva U
authors.initials: EU
authors.lastname: Wieckowski
authors.forename: Carmen
authors.initials: C
authors.lastname: Visus
authors.forename: Marta
authors.initials: M
authors.lastname: Szajnik
authors.forename: Miroslaw J
authors.initials: MJ
authors.lastname: Szczepanski
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
mesh_terms: D000951:Antigens, Neoplasm / Q000032:analysis; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055252:Cell-Derived Microparticles / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000032:analysis; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006801:Humans; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D009363:Neoplasm Proteins / Q000032:analysis; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D053222:Fas Ligand Protein; D015395:Histocompatibility Antigens Class I; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins
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