title: Effector Regulatory T Cells Reflect the Equilibrium between Antitumor Immunity and Autoimmunity in Adult T-cell Leukemia.
abstract: The regulatory T cells (Treg) with the most potent immunosuppressive activity are the effector Tregs (eTreg) with a CD45RA(-)Foxp3(++)CCR4(+) phenotype. Adult T-cell leukemia (ATL) cells often share the Treg phenotype and also express CCR4. Although mogamulizumab, a monoclonal antibody to CCR4, shows marked antitumor effects against ATL and peripheral T-cell lymphoma, concerns have been raised that it may induce severe autoimmune immunopathology by depleting eTregs. Here, we present case reports for two patients with ATL who responded to mogamulizumab but developed a severe skin rash and autoimmune brainstem encephalitis. Deep sequencing of the T-cell receptor revealed that ATL cells and naturally occurring Tregs within the cell population with a Treg phenotype can be clearly distinguished according to CADM1 expression. The onset of skin rash and brainstem encephalitis was coincident with eTreg depletion from the peripheral blood, whereas ATL relapses were coincident with eTreg recovery. These results imply that eTreg numbers in the peripheral blood sensitively reflect the equilibrium between antitumor immunity and autoimmunity, and that mogamulizumab might suppress ATL until the eTreg population recovers. Close monitoring of eTreg numbers is crucial if we are to provide immunomodulatory treatments that target malignancy without severe adverse events. Cancer Immunol Res; 4(8); 644-9. ©2016 AACR.
authors.affiliation: Department of Hematology, Respiratory Medicine and Oncology, Saga University School of Medicine, Saga, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ureshino
authors.affiliation: Department of Hematology, Respiratory Medicine and Oncology, Saga University School of Medicine, Saga, Japan. takeros@cc.saga-u.ac.jp.
authors.forename: Takero
authors.initials: T
authors.lastname: Shindo
authors.affiliation: Experimental Immunology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nishikawa
authors.affiliation: Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Watanabe
authors.affiliation: Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Satoh
authors.affiliation: Department of Clinical Immunology, Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, Sagamihara, Japan. Repertoire Genesis, Inc., Ibaraki, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Kitaura
authors.affiliation: Department of Hematology, Respiratory Medicine and Oncology, Saga University School of Medicine, Saga, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kitamura
authors.affiliation: Department of Dermatology, Karatsu Red Cross Hospital, Karatsu, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Doi
authors.affiliation: Department of Dermatology, Saga University School of Medicine, Saga, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Nagase
authors.affiliation: Department of Dermatology, Saga University School of Medicine, Saga, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Department of Neurology, Kinki University School of Medicine, Sayama, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Samukawa
authors.affiliation: Department of Neurology, Kinki University School of Medicine, Sayama, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kusunoki
authors.affiliation: Department of Internal Medicine, Karatsu Red Cross Hospital, Karatsu, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Miyahara
authors.affiliation: BITS Co. Ltd., Tokyo, Japan.
authors.forename: Tadasu
authors.initials: T
authors.lastname: Shin-I
authors.affiliation: Department of Clinical Immunology, Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, Sagamihara, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Experimental Immunology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita, Japan.
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.affiliation: Department of Hematology, Respiratory Medicine and Oncology, Saga University School of Medicine, Saga, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
mesh_terms: D000368:Aged; D015551:Autoimmunity; D015415:Biomarkers; D001706:Biopsy; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D003131:Combined Modality Therapy; D006801:Humans; D007109:Immunity; D016130:Immunophenotyping; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D008279:Magnetic Resonance Imaging; D008297:Male; D010641:Phenotype; D012867:Skin / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015415:Biomarkers