Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes.
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.
Tsuji
Takemasa
T
Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Yasukawa
Masaki
M
Matsuzaki
Junko
J
Ohkuri
Takayuki
T
Chamoto
Kenji
K
Wakita
Daiko
D
Azuma
Taichi
T
Niiya
Hironari
H
Miyoshi
Hiroyuki
H
Kuzushima
Kiyotaka
K
Oka
Yoshihiro
Y
Sugiyama
Haruo
H
Ikeda
Hiroaki
H
Nishimura
Takashi
T
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
D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D025721:WT1 Proteins; D007371:Interferon-gamma