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.