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Fas Ligand–Positive Membranous Vesicles Isolated from Sera of Patients with Oral Cancer Induce Apoptosis of Activated T Lymphocytes

¹ University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; ² University of Louisville School of Medicine, Louisville, Kentucky; and ³ University of Mainz, Mainz, Germany

Requests for reprints: Theresa L. Whiteside, University of Pittsburgh Cancer Institute, Research Pavilion at the Hillman Cancer Center, 5117 Centre Avenue, Suite 1.27, Pittsburgh, Pennsylvania 15213-1863. Phone: 412-624-0096; Fax: 412-624-0264; E-mail: whitesidetl{at}upmc.edu..

Objective: In patients with oral squamous cell carcinoma, a high proportion of T cells in the tumor undergo apoptosis, which correlates with Fas ligand (FasL) expression on tumor cells. The present study was done to identify mechanisms responsible for apoptosis of T cells seen in the peripheral circulation of these patients.

Methods: Sera of 27 patients, normal donor sera, and supernatants of cultured normal or tumor cells were fractionated by size exclusion chromatography and ultracentrifugation to isolate microvesicles. The presence of microvesicle-associated FasL was studied by Western blots, blocking with anti-Fas reagents, and immunoelectron microscopy. Biological activities of microvesicles were tested including the ability to induce apoptosis of Jurkat and T-cell blasts. Semiquantitative analysis of FasL in microvesicles was correlated with caspase-3 activity, DNA fragmentation, cytochrome c release, loss of mitochondrial membrane potential, and TCR- chain expression in lymphocytes.

Results: FasL-positive (FasL+) microvesicles were detected in sera of 21 of 27 patients. Microvesicles contained 42 kDa FasL. These microvesicles induced caspase-3 cleavage, cytochrome c release, loss of mitochondrial membrane potential, and reduced TCR- chain expression in target lymphocytes. Biological activity of the FasL+ microvesicles was partially blocked by ZB4 anti-Fas monoclonal antibody. Microvesicle-associated FasL levels correlated with the patients' tumor burden and nodal involvement.

Conclusion: Sera of patients with active oral squamous cell carcinoma contain FasL+ microvesicles, which induce the receptor and mitochondrial apoptotic pathways in Jurkat and activated T cells.

Key Words: cancer evasion • microvesicles • FasL • oral carcinoma

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