Identification of novel α-fetoprotein-specific T cell receptors to redirect human T cells for hepatocellular carcinoma immunotherapy
The Journal of Immunology(2018)
摘要
Abstract Hepatocellular carcinoma (HCC) is the major form of liver cancer for which there is no effective therapy. Genetic modification with T cell receptors (TCR) specific for HCC-associated antigens, such as α-fetoprotein (AFP), can potentially redirect human T cells to specifically recognize and kill HCC tumor cells to achieve antitumor effects. In this study, by using lentivector and peptide immunization, we identified a population of CD8-T cells in HLA-A2 transgenic AAD mice that recognized AFP158 epitope on human HCC cells. Adoptive transfer of the AFP158-specific CD8-T cells from immunized AAD mice eradicated HepG2 tumor xenografts as large as 2cm in diameter in immunocompromised NSG mice. We then established T cell hybridoma clones from the AFP158-specific mouse CD8-T cells and identified three sets of paired TCR genes out of 5 hybridomas. Expression of the murine TCR genes redirected primary human T cells to bind HLA-A2/AFP158 tetramer. The TCR gene-engineered human T cells (TCR-T) specifically recognized HLA-A2+AFP+ HepG2 tumor cells and produced effector cytokines. Importantly, the TCR-T cells could specifically kill HLA-A2+AFP+ HepG2 tumor cells without significant toxicity to normal hepatocytes in vitro. Adoptive transfer of the AFP-specific human TCR-T cells could eradicate HepG2 tumors in NSG mice. Conclusion We have identified novel AFP-specific murine TCR genes that can redirect human T cells to specifically recognize and kill HCC tumor cells, and those AFP158-specific TCRs have a great potential to engineer a patient’s autologous T cells to treat HCC tumors.
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