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  • Title: Levels of circulating regulatory CD4+CD25+ T cells are decreased in breast cancer patients after vaccination with a HER2/neu peptide (E75) and GM-CSF vaccine.
    Author: Hueman MT, Stojadinovic A, Storrer CE, Foley RJ, Gurney JM, Shriver CD, Ponniah S, Peoples GE.
    Journal: Breast Cancer Res Treat; 2006 Jul; 98(1):17-29. PubMed ID: 16758122.
    Abstract:
    PURPOSE: We are conducting clinical trials in breast cancer (BrCa) patients to test the HER2/neu peptide vaccine (E75). We have investigated the impact of this vaccine on circulating levels of regulatory T cells (Treg) and the resulting effects on antitumor responses. EXPERIMENTAL DESIGN: Twenty-two blood samples from healthy individuals and from 22 BrCa patients including pre- and post-vaccination samples from seven vaccinated HLA-A2+ patients were stained for CD4, CD25, and CD69 as well as CD8 and E75:HLA-A2 Ig dimer and quantified by flow cytometry. Cytotoxic activity against HER2/neu+ tumors was measured by 51Cr-release. Serum from BrCa patients and normal subjects were analyzed for TGF-beta levels. RESULTS: BrCa patients have a greater percentage of circulating Treg (CD4+CD25+, 4.45% versus 2.96%; p=0.007) than normal subjects. HLA-A2+ BrCa patients had more Treg compared to the HLA-A2- BrCa patients (CD4+CD25+, 5.63% versus 3.28%; p=0.001). E75 vaccination increased circulating activated CD4+ T cells post-vaccination (CD4+CD69+, 1.23 versus 3.81%; p=0.03). However, T(reg) were significantly reduced after vaccination (CD4+CD25+, 5.31-1.81%; p<0.0001). Furthermore, activated Treg also decreased (CD4+CD25+CD69+, 0.23% versus 0.08%; p=0.06). Importantly, post-vaccination decreases in Treg were temporally associated with increased E75 vaccine-specific CD8+ T cells and corresponding HER2/neu+ tumor cytotoxicity. Serum TGF-beta levels were significantly elevated in BrCa patients compared to normals (3548 pg/ml versus 1007 pg/ml; p=0.007). Four of seven vaccinated patients showed decreased serum TGF-beta levels post-vaccination. CONCLUSIONS: Treg, are increased in BrCa patients along with serum levels of TGF-beta. E75 vaccination resulted in CD4+ recruitment but was associated with a significant decrease in circulating Treg and TGF-beta levels in the majority of the vaccinated patients. Successful cancer vaccination strategies may require the alteration of complex immune interactions.
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