Identification of α-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy.
Hepatology
; 68(2): 574-589, 2018 08.
Article
in En
| MEDLINE
| ID: mdl-29443377
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).
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Alpha-Fetoproteins
/
Carcinoma, Hepatocellular
/
CD8-Positive T-Lymphocytes
/
Immunotherapy
/
Liver Neoplasms
Type of study:
Diagnostic_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Hepatology
Year:
2018
Document type:
Article
Affiliation country:
Gabón