Coexpression of the T-cell receptor constant alpha domain triggers tumor reactivity of single-chain TCR-transduced human T cells.

Détails

ID Serval
serval:BIB_C14D482CBBCF
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Coexpression of the T-cell receptor constant alpha domain triggers tumor reactivity of single-chain TCR-transduced human T cells.
Périodique
Blood
Auteur(s)
Voss R.H., Thomas S., Pfirschke C., Hauptrock B., Klobuch S., Kuball J., Grabowski M., Engel R., Guillaume P., Romero P., Huber C., Beckhove P., Theobald M.
ISSN
1528-0020[electronic], 0006-4971[linking]
Statut éditorial
Publié
Date de publication
2010
Volume
115
Numéro
25
Pages
5154-5163
Langue
anglais
Résumé
Transfer of tumor antigen-specific T-cell receptors (TCRs) into human T cells aims at redirecting their cytotoxicity toward tumors. Efficacy and safety may be affected by pairing of natural and introduced TCRalpha/beta chains potentially leading to autoimmunity. We hypothesized that a novel single-chain (sc)TCR framework relying on the coexpression of the TCRalpha constant alpha (Calpha) domain would prevent undesired pairing while preserving structural and functional similarity to a fully assembled double-chain (dc)TCR/CD3 complex. We confirmed this hypothesis for a murine p53-specific scTCR. Substantial effector function was observed only in the presence of a murine Calpha domain preceded by a TCRalpha signal peptide for shuttling to the cell membrane. The generalization to a human gp100-specific TCR required the murinization of both C domains. Structural and functional T-cell avidities of an accessory disulfide-linked scTCR gp100/Calpha were higher than those of a dcTCR. Antigen-dependent phosphorylation of the proximal effector zeta-chain-associated protein kinase 70 at tyrosine 319 was not impaired, reflecting its molecular integrity in signaling. In melanoma-engrafted nonobese diabetic/severe combined immunodeficient mice, adoptive transfer of scTCR gp100/Calpha transduced T cells conferred superior delay in tumor growth among primary and long-term secondary tumor challenges. We conclude that the novel scTCR constitutes a reliable means to immunotherapeutically target hematologic malignancies.
Mots-clé
Adoptive Transfer, Animals, Antigens, Neoplasm/genetics, Antigens, Neoplasm/immunology, Cell Line, Tumor, Humans, Immunity, Cellular, Melanoma/genetics, Melanoma/immunology, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Transplantation, Phosphorylation/genetics, Protein Structure, Tertiary, Receptors, Antigen, T-Cell, alpha-beta/biosynthesis, Receptors, Antigen, T-Cell, alpha-beta/genetics, T-Lymphocytes/immunology, T-Lymphocytes/metabolism, Transduction, Genetic, Tumor Suppressor Protein p53/genetics, Tumor Suppressor Protein p53/immunology
Pubmed
Web of science
Open Access
Oui
Création de la notice
02/02/2011 10:28
Dernière modification de la notice
20/08/2019 15:36
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