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Increased Populations of Regulatory T Cells in Peripheral Blood and Tumor-Infiltrating Lymphocytes in Patients with Gastric and Esophageal Cancers

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

Purpose: It is well known that tumor-infiltrating lymphocytes (TILs) and, to a lesser extent, peripheral blood lymphocytes from patients with advanced-stage cancer have a poor immune response. Regulatory T cells (T-regs), characterized by coexpression of CD4 and CD25 markers, can inhibit the immune response mediated by CD4+/CD25- and CD8+ T cells. In the present study, we evaluated the prevalence of T-regs in peripheral blood and TILs in patients with gastric and esophageal cancers.

Experimental Design: The population of CD4+/CD25+ cells as a percentage of total CD3+ cells was evaluated by flow cytometric analysis with triple-color staining. To assess the functional activity of CD4+/CD25+ cells, CD4+/CD25+ or CD4+/CD25- cells were purified from peripheral blood mononuclear cells with magnetic beads. The cytokine production [interleukin (IL)-10 and IFN-] from the CD4+/CD25+ cells in response to anti-CD3 stimulation was evaluated. Also, the antiproliferative function of CD4+/CD25+ cells was measured by evaluating the proliferative activity of CD4+/CD25- cells in response to anti-CD3 plus anti-CD28 in the presence of autologous CD4+/CD25+ cells.

Results: The prevalence of peripheral blood CD4+/CD25+ cells in both gastric (n = 20; 14.2 ± 4.9%) and esophageal cancer patients (n = 10; 19.8 ± 6.9%) was significantly higher than that in healthy donors (n = 16; 7.2 ± 2.1%). The population of CD4+/CD25+ cells in the TILs of gastric cancer patients with advanced disease (19.8 ± 4.5%) was significantly higher than that in TILs of patients with early-stage disease (4.8 ± 2.1%) or that in intraepithelial lymphocytes of normal gastric mucosa (4.0 ± 1.2%). As a functional consequence, CD4+/CD25+ cells did not produce IFN-, whereas CD4+/CD25- cells secreted IFN-. Moreover, CD4+/CD25+ cells produced large amounts of IL-10, whereas CD4+/CD25- cells secreted little IL-10. The proliferation of CD4+/CD25- cells was inhibited in the presence of CD4+/CD25+ cells in a dose-dependent manner, confirming that CD4+/CD25+ has an inhibitory activity corresponding to T-regs.

Conclusions: The populations of CD4+/CD25+ T-regs in peripheral blood and TILs in patients with gastric and esophageal cancers were significantly higher in comparison with those in healthy donors or normal mucosa.

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