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: Takemasa Tsuji, Masaki Yasukawa, Junko Matsuzaki, Takayuki Ohkuri, Kenji Chamoto, Daiko Wakita, Taichi Azuma, Hironari Niiya, Hiroyuki Miyoshi, Kiyotaka Kuzushima, Yoshihiro Oka, Haruo Sugiyama, Hiroaki Ikeda, Takashi Nishimura
• Journal: Blood (Blood) Vol. 106 Issue 2 Pg. 470-6 (Jul 15 2005) ISSN: 0006-4971 [Print] United States
• PMID: 15790789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-A Antigens
• HLA-A24 Antigen
• Neoplasm Proteins
• Receptors, Antigen, T-Cell
• WT1 Proteins
• Interferon-gamma

Topics

• Cytotoxicity, Immunologic
• Genetic Engineering
• HLA-A Antigens (metabolism)
• HLA-A24 Antigen
• Humans
• In Vitro Techniques
• Interferon-gamma (biosynthesis)
• Lentivirus (genetics)
• Leukemia (genetics, immunology, therapy)
• Neoplasm Proteins (genetics, immunology)
• Neoplasms (genetics, immunology)
• Receptors, Antigen, T-Cell (genetics)
• T-Lymphocyte Subsets (immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Th1 Cells (immunology)
• Transduction, Genetic
• WT1 Proteins (genetics, immunology)