Depletion of Regulatory T Lymphocytes Reverses the Imbalance between Pro- and Anti-Tumor Immunities via Enhancing Antigen-Specific T Cell Immune Responses
Journal
PLoS ONE
Journal Volume
7
Journal Issue
10
Pages
e47190
Date Issued
2012
Author(s)
Abstract
Background: The regulatory T cells (Tregs) can actively suppress the immune responses. However, literature about detailed changes of host effective and suppressive immunities before and after depletion of Tregs in ovarian carcinomas, is rare. Materials and Methods: Ovarian cancer patients and the ascitogenic animal model were employed. Immunologic profiles with flow cytometric analyses, immunohistochemistric staining, RT-PCR, ELISA, and ELISPOT assays were performed. In vivo depletion of Treg cells with the mAb PC61was also performed in the animal model. Results: The cytokines, including IL-4 (p = 0.017) and TNF-α (p = 0.046), significantly decreased while others such as TGF-β (p = 0.013), IL-6 (p = 0.016), and IL-10 (p = 0.018) were elevated in ascites of ovarian cancer patients, when the disease progressed to advanced stages. The ratio of CD8+ T cell/Treg cell in ascites was also lower in advanced diseases than in early diseases (advanced 7.37±0.64 vs. early 14.25±3.11, p = 0.037). The kinetic low-dose CD25 Ab depletion group had significantly lower intra-peritoneal tumor weight (0.20±0.03 g) than the sequential high-dose (0.69±0.06 g) and sequential low-dose (0.67±0.07 g) CD25 Ab deletion groups (p = 0.001) after 49 days of tumor challenge in the animal. The kinetic low-dose CD25 Ab depletion group generated the highest number of IFN-γ-secreting, mesothelin-specific T lymphocytes compared to the other groups (p<0.001). Conclusions: The imbalance between effective and suppressive immunities becomes more severe as a tumor progresses. The depletion of Treg cells can correct the imbalance of immunologic profiles and generate potent anti-tumor effects. Targeting Treg cells can be a new strategy for the immunotherapy of ovarian carcinoma. ? 2012 Chen et al.
SDGs
Other Subjects
CD4 antigen; CD8 antigen; gamma interferon; interleukin 10; interleukin 12; interleukin 13; interleukin 17; interleukin 2 receptor alpha; interleukin 4; interleukin 5; interleukin 6; interleukin 9; mesothelin; monoclonal antibody; transcription factor FOXP3; transforming growth factor beta; tumor necrosis factor alpha; animal cell; animal experiment; animal model; antigen specificity; article; ascites; cancer staging; CD8+ T lymphocyte; cellular immunity; clinical article; controlled study; cytokine release; disease course; disease model; disease severity; enzyme linked immunosorbent assay; enzyme linked immunospot assay; female; flow cytometry; human; human cell; human tissue; immunohistochemistry; in vivo study; lymphocyte depletion; mouse; nonhuman; ovary cancer; regulatory T lymphocyte; reverse transcription polymerase chain reaction; T lymphocyte; tumor immunity; tumor volume; Animals; Antibodies, Monoclonal; Antibodies, Neoplasm; Antigens, Neoplasm; Ascites; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cytokines; Disease Progression; Dose-Response Relationship, Immunologic; Female; Humans; Immunity; Interleukin-2 Receptor alpha Subunit; Kinetics; Lymphocyte Activation; Lymphocyte Depletion; Mice; Mice, Inbred C57BL; Neoplasm Staging; Ovarian Neoplasms; Spleen; T-Lymphocytes, Regulatory; Tumor Microenvironment
Type
journal article