Suppressive activity rather than frequency of FoxP3(+) regulatory T cells is essential for CA-125-specific T-cell activation after abagovomab treatment.
The results of several clinical trials have clearly demonstrated the potential of the anti-idiotype (anti-Id) vaccine abagovomab to induce cancer antigen 125 (CA-125)-specific immunity in ovarian cancer patients. Because of the central role of regulatory T cells (Tregs) in tumor immunology, we analyzed the frequency and suppressive activity of CD25(+)FoxP3(+) Tregs in 16 patients treated with abagovomab. During vaccination, mean frequencies of peripheral Treg with a CD4(+)CD25(+)FoxP3(+) CD127(-) phenotype were enhanced but returned to baseline levels in the follow-up phase. Despite increasing Treg counts, the suppressive activity of Tregs was diminished in a subset of patients treated with abagovomab. Reduced Treg activity was associated with increasing polyclonal and CA-125-specific T-cell proliferation in these patients. Interestingly, CA-125-specific T-cell activation could not be further improved by Treg depletion in vitro, as CA-125 induced a suppressive CD4(+)CD25(+)FoxP3(+) CD127(-) T cell subset derived from the originally Treg-depleted T-cell fraction. These CA-125-induced Tregs (iTregs) efficiently blocked polyclonal and tumor-specific T-cell activation. Further elimination of iTregs resulted in detectable CA-125-specific T-cell responses in a subset of patients. Based on our results, the suppressive potential rather than the frequency of natural and CA-125-induced Tregs is an important issues to consider for refinement of current anti-Id vaccination.
Klinik für Gynäkologie, Gyn. Endokrinologie und Onkologie, Universitätsklinikum, Giessen und Marburg, GmbH, 35043 Marburg, Germany. reinartz@med.uni-marburg.de
Silke
S
Reinartz
Jacobus
J
Pfisterer
Andreas
A
du Bois
Christian
C
Jackisch
Klaus H
KH
Baumann
Uwe
U
Wagner
D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D018394:CA-125 Antigen / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018394:CA-125 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C518318:abagovomab