title: The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-Cell leukemia/lymphoma.
abstract: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm with dismal prognosis, and no optimal therapy has been developed. We tested the defucosylated chimeric anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, KM2760, to develop a novel immunotherapy for this refractory tumor. In the presence of peripheral blood mononuclear cells (PBMCs) from healthy adult donors, KM2760 induced CCR4-specific antibody-dependent cellular cytotoxicity (ADCC) against CCR4-positive ATLL cell lines and primary tumor cells obtained from ATLL patients. We next examined the KM2760-induced ADCC against primary ATLL cells in an autologous setting. Antibody-dependent cellular cytotoxicity mediated by autologous effector cells was generally lower than that mediated by allogeneic control effector cells. However, a robust ADCC activity was induced in some cases, which was comparable with that mediated by allogeneic effector cells. It suggests that the ATLL patients' PBMCs retain substantial ADCC-effector function, although the optimal conditions for maximal effect have not yet been determined. In addition, we also found a high expression of FoxP3 mRNA and protein, a hallmark of regulatory T cells, in ATLL cells, indicating the possibility that ATLL cells originated from regulatory T cells. KM2760 reduced FoxP3 mRNA expression in normal PBMCs along with CCR4 mRNA by lysis of CCR4+ T cells in vitro. Our data suggest not only that the CCR4 molecule could be a suitable target for the novel antibody-based therapy for patients with ATLL but also that KM2760 may induce effective tumor immunity by reducing the number of regulatory T cells.
authors.affiliation: Department of Internal Medicine & Molecular Science, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishida
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Akatsuka
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ishii
authors.forename: Mikinori
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Komatsu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inagaki
authors.forename: Noriko
authors.initials: N
authors.lastname: Okada
authors.forename: Teizo
authors.initials: T
authors.lastname: Fujita
authors.forename: Kenya
authors.initials: K
authors.lastname: Shitara
authors.forename: Shiro
authors.initials: S
authors.lastname: Akinaga
authors.forename: Toshitada
authors.initials: T
authors.lastname: Takahashi
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ueda
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry; D015153:Blotting, Western; D017252:CD3 Complex / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors; D005838:Genotype; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D012333:RNA, Messenger / Q000378:metabolism; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000911:Antibodies, Monoclonal; C515354:CCR4 protein, human; D017252:CD3 Complex; D004268:DNA-Binding Proteins; C496124:FCGR3A protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D017452:Receptors, IgG