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

• Published in: Clinical cancer research 2003-10, Vol.9 (12), p.4404-4408
• Main Authors: ICHIHARA, Fumiko, KONO, Koji, TAKAHASHI, Akihiro, KAWAIDA, Hiromichi, SUGAI, Hidemitsu, FUJII, Hideki
• Format: Article
• Language: English
• Subjects: Aged; Biological and medical sciences; Case-Control Studies; CD4 Antigens - immunology; CD4 Antigens - metabolism; Cell Division - immunology; Esophageal Neoplasms - blood; Esophageal Neoplasms - immunology; Esophageal Neoplasms - pathology; Female; Gastric Mucosa - immunology; Gastric Mucosa - metabolism; Gastric Mucosa - pathology; Host-tumor relations. Immunology. Biological markers; Humans; Immune System - physiology; Immune Tolerance; Interferon-gamma - biosynthesis; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - pathology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - pathology; Male; Medical sciences; Middle Aged; Receptors, Interleukin-2 - immunology; Receptors, Interleukin-2 - metabolism; Stomach Neoplasms - blood; Stomach Neoplasms - immunology; Stomach Neoplasms - pathology; T-Lymphocytes - immunology; Tumors
• ISSN: 1078-0432; 1557-3265

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-γ] 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-γ, whereas CD4+/CD25− cells secreted IFN-γ. 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.