Tumor-Derived Microvesicles Promote Regulatory T Cell Expansion and Induce Apoptosis in Tumor-Reactive Activated CD8+ T Lymphocytes1

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.