title: Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans.
abstract: CD4(+) Treg cells expressing the transcription factor FOXP3 (forkhead box P3) are abundant in tumor tissues and appear to hinder the induction of effective antitumor immunity. A substantial number of T cells, including Treg cells, in tumor tissues and peripheral blood express C-C chemokine receptor 4 (CCR4). Here we show that CCR4 was specifically expressed by a subset of terminally differentiated and most suppressive CD45RA(-)FOXP3(hi)CD4(+) Treg cells [designated effector Treg (eTreg) cells], but not by CD45RA(+)FOXP3(lo)CD4(+) naive Treg cells, in peripheral blood of healthy individuals and cancer patients. In melanoma tissues, CCR4(+) eTreg cells were predominant among tumor-infiltrating FOXP3(+) T cells and much higher in frequency compared with those in peripheral blood. With peripheral blood lymphocytes from healthy individuals and melanoma patients, ex vivo depletion of CCR4(+) T cells and subsequent in vitro stimulation of the depleted cell population with the cancer/testis antigen NY-ESO-1 efficiently induced NY-ESO-1-specific CD4(+) T cells. Nondepletion failed in the induction. The magnitude of the responses was comparable with total removal of FOXP3(+) Treg cells by CD25(+) T-cell depletion. CCR4(+) T-cell depletion also augmented in vitro induction of NY-ESO-1-specific CD8(+) T cells in melanoma patients. Furthermore, in vivo administration of anti-CCR4 mAb markedly reduced the eTreg-cell fraction and augmented NY-ESO-1-specific CD8(+) T-cell responses in an adult T-cell leukemia-lymphoma patient whose leukemic cells expressed NY-ESO-1. Collectively, these findings indicate that anti-CCR4 mAb treatment is instrumental for evoking and augmenting antitumor immunity in cancer patients by selectively depleting eTreg cells.
authors.affiliation: Experimental Immunology, World Premier International Research Center, Immunology Frontier Research Center, Department of Dermatology, and Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sugiyama
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Yuka
authors.initials: Y
authors.lastname: Maeda
authors.forename: Megumi
authors.initials: M
authors.lastname: Nishioka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanemura
authors.forename: Ichiro
authors.initials: I
authors.lastname: Katayama
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ezoe
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kanakura
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sato
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Fukumori
authors.forename: Julia
authors.initials: J
authors.lastname: Karbach
authors.forename: Elke
authors.initials: E
authors.lastname: Jäger
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D058501:Enzyme-Linked Immunospot Assay; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D054398:Receptors, CCR4 / Q000276:immunology; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C515354:CCR4 protein, human; C104948:CTAG1B protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D054398:Receptors, CCR4
keywords: cancer immunotherapy; immunomodulation