Identification of α-fetoprotein-specific T cell receptors for hepatocellular carcinoma immunotherapy

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 mouse CD8-T cells 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) also specifically recognized HLA-A2⁺AFP⁺ HepG2 HCC 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 primary 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. This article is protected by copyright. All rights reserved.

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