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The CD4⁺ T-Cell Response of Melanoma Patients to a MAGE-A3 Peptide Vaccine Involves Potential Regulatory T Cells

¹ Université Catholique de Louvain, Ludwig Institute for Cancer Research Ltd., ² Université Catholique de Louvain, de Duve Institute, Cellular Genetics Unit, and ³ Laboratory of Physiology-Immunology, Vrije Universiteit Brussel, Brussels, Belgium and ⁴ Department of Dermatology, University Hospital Erlangen, Erlangen, Germany

Requests for reprints: Pierre van der Bruggen, Ludwig Institute for Cancer Research, 74 av. Hippocrate, UCL7459, B-1200 Brussels, Belgium. Phone: 32-2-7647431; Fax: 32-2-7629405; E-mail: pierre.vanderbruggen{at}bru.licr.org.

Key Words: vaccine • regulatory T cells • CD4 • T cell response • FOXP3

Melanoma patients were injected with various vaccines containing a MAGE-A3 peptide presented by HLA-DP4. Anti–MAGE-A3.DP4 T cells were not detectable in the blood before vaccination, but their frequencies after vaccination ranged from 2 x 10^–6 to 2 x 10^–3 among the CD4⁺ blood T lymphocytes of the patients. The CD4⁺ blood T lymphocytes that stained ex vivo with HLA-DP4 tetramers folded with the MAGE-A3 peptide were selected by flow cytometry and amplified under clonal conditions. About 5% of the CD4⁺ T-cell clones that recognized the MAGE-A3.DP4 antigen had a CD25⁺ phenotype in the resting state. These CD25⁺ clones had a high capacity to suppress the proliferation of another T-cell clone after peptide stimulation in vitro. Most of them had high FOXP3 expression in the resting state and an unmethylated FOXP3 intron 1. They produced active transforming growth factor-β but none of cytokines IFN-, interleukin-2 (IL-2), IL-4, IL-5, and IL-10. About 20% of CD25^– clones had a significant but lower suppressive activity. Most of the CD25^– clonal populations contained cells that expressed FOXP3 in the resting state, but FOXP3 demethylation was not observed. We conclude that MAGE-A3.DP4 vaccination can produce CD4⁺ T cells that may exert regulatory T-cell function in vivo. [Cancer Res 2009;69(10):4335–45]