title: Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes.
abstract: Tumor antigen-specific CD4+ and CD8+ T lymphocytes, especially interferon-gamma (IFN-gamma)-producing type-1 helper T (Th1) and type-1 cytotoxic T (Tc1) cells, play a crucial role in tumor eradication. Adoptive transfer using tumor-specific Th1 and Tc1 cells is a promising therapeutic strategy for tumor immunotherapy. However, its clinical application has been hampered because of difficulties in generating tumor-specific Th1 cells from patients with tumors. To overcome this problem, we have developed an efficient method to prepare tumor-specific Th1 and Tc1 cells. T-cell receptor (TCR) alpha and beta genes obtained from an HLA-A24-restricted, Wilms tumor 1 (WT1) peptide-specific Tc clone were lentivirally transduced to polyclonally activated Th1 and Tc1 cells. As expected, TCR gene-modified Tc1 cells showed cytotoxicity and IFN-gamma production in response to peptide-loaded lymphoblastoid cell lines, WT1 gene-transduced cells, and freshly isolated leukemia cells expressing both WT1 and HLA-A24. Surprisingly, we further demonstrated that Th1 cells transduced with HLA-class I-restricted TCR genes also showed both cytotoxicity and cytokine production in an HLA-A24-restricted manner. In contrast to gene-modified Tc1 cells, Th1 cells produced high amounts of interleukin-2 (IL-2) in addition to IFN-gamma, which is beneficial for induction of antitumor cellular immunity. Thus, TCR gene-modified HLA-class I-restricted Th1 and Tc1 cells are a powerful strategy for the application to adoptive immunotherapy of human cancer.
authors.affiliation: Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Takemasa
authors.initials: T
authors.lastname: Tsuji
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuzaki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ohkuri
authors.forename: Kenji
authors.initials: K
authors.lastname: Chamoto
authors.forename: Daiko
authors.initials: D
authors.lastname: Wakita
authors.forename: Taichi
authors.initials: T
authors.lastname: Azuma
authors.forename: Hironari
authors.initials: H
authors.lastname: Niiya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyoshi
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kuzushima
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Oka
authors.forename: Haruo
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ikeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishimura
mesh_terms: D003602:Cytotoxicity, Immunologic; D005818:Genetic Engineering; D015234:HLA-A Antigens / Q000378:metabolism*; D059871:HLA-A24 Antigen; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D016086:Lentivirus / Q000235:genetics; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000628:therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014161:Transduction, Genetic; D025721:WT1 Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D025721:WT1 Proteins; D007371:Interferon-gamma