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Elevated Caspase-3 Activity in Peripheral Blood T Cells Coexists with Increased Degree of T-Cell Apoptosis and Down-Regulation of TCR Zeta Molecules in Patients with Gastric Cancer¹

First Department of Surgery, Yamanashi Medical University, Yamanashi 409-3898, Japan

To evaluate the mechanisms of T-cell dysfunction in patients with gastric cancer, we investigated the caspase activity of T cells, the induction of spontaneous T-cell apoptosis, the expression of T-cell receptor (TCR) molecules, and the ability of T cells to produce cytokines in peripheral blood lymphocytes from patients (n = 22) and healthy controls (n = 14). The caspase-3 activity of T cells was studied as the protease activity of caspase-3 using the cell-permeable substrate of PhiPhiLux G1D2. Flow cytometric analysis was performed with triple staining by annexin V-FITC, propidium iodide, and CD3-R-phycoerythrin-Cy5 for the detection of T-cell apoptosis and with intracellular staining using permeabilized cells for the expression of TCR- molecules. IFN- and tumor necrosis factor production from T cells was evaluated in response to anti-CD3 stimulation. Caspase-3 activity of peripheral blood T cells from patients with advanced disease was significantly increased compared with that from controls [15.5 ± 3.6 mean fluorescence intensity (MFI) versus 11.5 ± 3.3 MFI; P = 0.0068]. Parallel to this, the apoptosis of peripheral blood T cells from patients with advanced disease was significantly higher than for those from controls (16.5 ± 15.5% versus 4.8 ± 2.7%; P = 0.010). Furthermore, the expression of TCR- molecules in patients with advanced disease was significantly decreased in comparison with that of the controls (41.0 ± 13.9 MFI versus 56.7 ± 16.3 MFI; P = 0.014), and this decreased expression coexisted with impaired IFN- (42.4 ± 43.2 pg/ml versus 1757.4 ± 2449.0 pg/ml; P = 0.031) and tumor necrosis factor (682.6 ± 519.3 pg/ml versus 1686.0 ± 1533.7 pg/ml; P = 0.041) production of T cells. Thus, peripheral blood T cells from gastric cancer patients simultaneously exhibit an elevated caspase-3 activity, an increased degree of T-cell apoptosis, a down-regulation of TCR- molecules, and impaired cytokine production. These observations suggest that induction of T-cell apoptosis coexisting with a down-regulation of TCR- molecules may be responsible for T-cell dysfunction in patients with gastric cancer.

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