Preservation and redirection of HPV16E7-specific T cell receptors for immunotherapy of cervical cancer.
Clin Immunol
; 114(2): 119-29, 2005 Feb.
Article
em En
| MEDLINE
| ID: mdl-15639645
ABSTRACT
Human papilloma virus (HPV) type 16 infections of the genital tract are associated with the development of cervical cancer (CxCa) in women. HPV16-derived oncoproteins E6 and E7 are expressed constitutively in these lesions and might therefore be attractive candidates for T-cell-mediated adoptive immunotherapy. However, the low precursor frequency of HPV16E7-specific T cells in patients and healthy donors hampers routine isolation of these cells for adoptive transfer. To overcome this problem, we have isolated T cell receptor (TCR) genes from four different HPV16E7-specific healthy donor and patient-derived human cytotoxic T lymphocyte (CTL) clones. We examined whether genetic engineering of peripheral blood-derived CD8+ T cells in order to express HPV16E711-20-specific TCRs is feasible for adoptive transfer purposes. Reporter cells (Jurkat/MA) carrying a transgenic TCR were shown to bind relevant but not irrelevant tetramers. Moreover, these TCR-transgenic Jurkat/MA cells showed reactivity towards relevant target cells, indicating proper functional activity of the TCRs isolated from already available T cell clones. We next introduced an HPV16E711-20-specific TCR into blood-derived, CD8+ recipient T cells. Transgenic CTL clones stained positive for tetramers presenting the relevant HPV16E711-20 epitope and biological activity of the TCR in transduced CTL was confirmed by lytic activity and by interferon (IFN)-gamma secretion upon antigen-specific stimulation. Importantly, we show recognition of the endogenously processed and HLA-A2 presented HPV16E711-20 CTL epitope by A9-TCR-transgenic T cells. Collectively, our data indicate that HPV16E7 TCR gene transfer is feasible as an alternative strategy to generate human HPV16E7-specific T cells for the treatment of patients suffering from cervical cancer and other HPV16-induced malignancies.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Papillomaviridae
/
Receptores de Antígenos de Linfócitos T
/
Neoplasias do Colo do Útero
/
Proteínas Oncogênicas Virais
/
Imunoterapia Adotiva
/
Infecções por Papillomavirus
Limite:
Female
/
Humans
Idioma:
En
Revista:
Clin Immunol
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2005
Tipo de documento:
Article
País de afiliação:
Holanda