title: A cancer vaccine induces expansion of NY-ESO-1-specific regulatory T cells in patients with advanced melanoma.
abstract: Cancer vaccines are designed to expand tumor antigen-specific T cells with effector function. However, they may also inadvertently expand regulatory T cells (Treg), which could seriously hamper clinical efficacy. To address this possibility, we developed a novel assay to detect antigen-specific Treg based on down-regulation of surface CD3 following TCR engagement, and used this approach to screen for Treg specific to the NY-ESO-1 tumor antigen in melanoma patients treated with the NY-ESO-1/ISCOMATRIX™ cancer vaccine. All patients tested had Treg (CD25(bright) FoxP3(+) CD127(neg)) specific for at least one NY-ESO-1 epitope in the blood. Strikingly, comparison with pre-treatment samples revealed that many of these responses were induced or boosted by vaccination. The most frequently detected response was toward the HLA-DP4-restricted NY-ESO-1(157-170) epitope, which is also recognized by effector T cells. Notably, functional Treg specific for an HLA-DR-restricted epitope within the NY-ESO-1(115-132) peptide were also identified at high frequency in tumor tissue, suggesting that NY-ESO-1-specific Treg may suppress local anti-tumor immune responses. Together, our data provide compelling evidence for the ability of a cancer vaccine to expand tumor antigen-specific Treg in the setting of advanced cancer, a finding which should be given serious consideration in the design of future cancer vaccine clinical trials.
authors.affiliation: Ludwig Institute for Cancer Research (Melbourne-Austin Branch), Melbourne, Australia.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ebert
authors.forename: Sarah E
authors.initials: SE
authors.lastname: MacRaild
authors.forename: Damien
authors.initials: D
authors.lastname: Zanker
authors.forename: Ian D
authors.initials: ID
authors.lastname: Davis
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
mesh_terms: D019496:Cancer Vaccines / Q000627:therapeutic use*; D002478:Cells, Cultured; D000939:Epitopes / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D000939:Epitopes