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

Wei Zhu, Yibing Peng, Lan Wang, Yuan Hong, Xiaotao Jiang, Qi Li, Heping Liu, Lei Huang, Juan Wu, Esteban Celis, Todd David Merchen, Edward James Kruse, Yukai He

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) is the major form of liver cancer for which there is no effective therapy. Genetic modification with T-cell receptors (TCRs) 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, using lentivector and peptide immunization, we identified a population of cluster of differentiation 8 (CD8) T cells in human leukocyte antigen (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 2 cm in diameter in immunocompromised nonobese diabetic severe combined immunodeficient gamma knockout (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 five hybridomas. Expression of the murine TCR genes redirected primary human T cells to bind HLA-A2/AFP158 tetramer. TCR gene-engineered human T (TCR-T) cells 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 TCR-T cells could eradicate HepG2 tumors in NSG mice. Conclusion: We have identified 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. (Hepatology 2018).

Original languageEnglish (US)
Pages (from-to)574-589
Number of pages16
JournalHepatology
Volume68
Issue number2
DOIs
StatePublished - Aug 2018

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Fetal Proteins
T-Cell Antigen Receptor
Immunotherapy
Hepatocellular Carcinoma
T-Lymphocytes
T-Cell Receptor Genes
HLA Antigens
varespladib methyl
Neoplasms
Adoptive Transfer
Hybridomas
Tumor-Associated Carbohydrate Antigens
Hep G2 Cells
Gastroenterology
Liver Neoplasms
Heterografts
Knockout Mice
Transgenic Mice
Epitopes
Hepatocytes

ASJC Scopus subject areas

  • Hepatology

Cite this

Identification of α-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy. / Zhu, Wei; Peng, Yibing; Wang, Lan; Hong, Yuan; Jiang, Xiaotao; Li, Qi; Liu, Heping; Huang, Lei; Wu, Juan; Celis, Esteban; Merchen, Todd David; Kruse, Edward James; He, Yukai.

In: Hepatology, Vol. 68, No. 2, 08.2018, p. 574-589.

Research output: Contribution to journalArticle

Zhu, Wei ; Peng, Yibing ; Wang, Lan ; Hong, Yuan ; Jiang, Xiaotao ; Li, Qi ; Liu, Heping ; Huang, Lei ; Wu, Juan ; Celis, Esteban ; Merchen, Todd David ; Kruse, Edward James ; He, Yukai. / Identification of α-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy. In: Hepatology. 2018 ; Vol. 68, No. 2. pp. 574-589.
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abstract = "Hepatocellular carcinoma (HCC) is the major form of liver cancer for which there is no effective therapy. Genetic modification with T-cell receptors (TCRs) 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, using lentivector and peptide immunization, we identified a population of cluster of differentiation 8 (CD8) T cells in human leukocyte antigen (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 2 cm in diameter in immunocompromised nonobese diabetic severe combined immunodeficient gamma knockout (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 five hybridomas. Expression of the murine TCR genes redirected primary human T cells to bind HLA-A2/AFP158 tetramer. TCR gene-engineered human T (TCR-T) cells 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 TCR-T cells could eradicate HepG2 tumors in NSG mice. Conclusion: We have identified 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. (Hepatology 2018).",
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