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

AbstractTumor antigen–specific CD4+ and CD8+ T lymphocytes, especially interferon-γ (IFN-γ)–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) α and β 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-γ 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-γ, 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.