Depletion of regulatory T lymphocytes reverses the imbalance between pro- and anti-tumor immunities via enhancing antigen-specific T cell immune responses.
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.


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.
Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Yu-Li
YL
Chen
Ming-Cheng
MC
Chang
Chi-An
CA
Chen
Han-Wei
HW
Lin
Wen-Fang
WF
Cheng
Chung-Liang
CL
Chien
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D001201:Ascites / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D007109:Immunity / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D000090204:Mesothelin; D051379:Mice; D008810:Mice, Inbred C57BL; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; C000715528:Msln protein, mouse; D000090204:Mesothelin