title: BCR-ABL-specific CD4+T-helper cells promote the priming of antigen-specific cytotoxic T cells via dendritic cells.
abstract: The advent of tyrosine kinase inhibitor (TKI) therapy markedly improved the outcome of patients with chronic-phase chronic myeloid leukemia (CML). However, the poor prognosis of patients with advanced-phase CML and the lifelong dependency on TKIs are remaining challenges; therefore, an effective therapeutic has been sought. The BCR-ABL p210 fusion protein's junction region represents a leukemia-specific neoantigen and is thus an attractive target for antigen-specific T-cell immunotherapy. BCR-ABL p210 fusion-region-specific CD4+T-helper (Th) cells possess antileukemic potential, but their function remains unclear. In this study, we established a BCR-ABL p210 b3a2 fusion-region-specific CD4+Th-cell clone (b3a2-specific Th clone) and examined its dendritic cell (DC)-mediated antileukemic potential. The b3a2-specific Th clone recognized the b3a2 peptide in the context of HLA-DRB1*09:01 and exhibited a Th1 profile. Activation of this clone through T-cell antigen receptor stimulation triggered DC maturation, as indicated by upregulated production of CD86 and IL-12p70 by DCs, which depended on CD40 ligation by CD40L expressed on b3a2-specific Th cells. Moreover, in the presence of HLA-A*24:02-restricted Wilms tumor 1 (WT1)235-243peptide, DCs conditioned by b3a2-specific Th cells efficiently stimulated the primary expansion of WTI-specific cytotoxic T lymphocytes (CTLs). The expanded CTLs were cytotoxic toward WT1235-243-peptide-loaded HLA-A*24:02-positive cell lines and exerted a potent antileukemic effect in vivo. However, the b3a2-specific Th-clone-mediated antileukemic CTL responses were strongly inhibited by both TKIs and interferon-α. Our findings indicate a crucial role of b3a2-specific Th cells in leukemia antigen-specific CTL-mediated immunity and provide an experimental basis for establishing novel CML immunotherapies.
authors.affiliation: Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-0021, Japan.|Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.|Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-0065, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Ueda
authors.affiliation: Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-0021, Japan.|Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-0021, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Tatsumi
authors.affiliation: Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-0021, Japan.|Key Laboratory of Cancer Center, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Tian-Yi
authors.initials: TY
authors.lastname: Liu
authors.affiliation: Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kitayama
authors.affiliation: Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yasui
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Sugai
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Iwama
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Senju
authors.affiliation: Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakatsura
authors.affiliation: Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-0021, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kuzushima
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-0065, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
authors.affiliation: National Hospital Organization Nagoya Medical Center, Nagoya 460-0001, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
authors.affiliation: Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-0021, Japan.|Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Uemura
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D059810:HLA-DR Serological Subtypes / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis; D007938:Leukemia / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000494:pharmacology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*
chemical_list: D000939:Epitopes; D059810:HLA-DR Serological Subtypes; C038988:HLA-DR9 antigen; D016898:Interferon-alpha; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011948:Receptors, Antigen, T-Cell; D018664:Interleukin-12; D016044:Fusion Proteins, bcr-abl