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Coexpression of the T-cell receptor constant α domain triggers tumor reactivity of single-chain TCR-transduced human T cells
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Titel: |
Coexpression of the T-cell receptor constant α domain triggers tumor reactivity of single-chain TCR-transduced human T cells |
In: | Blood, 115, 2010, 25, S. 5154-5163 |
veröffentlicht: |
American Society of Hematology
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Umfang: | 5154-5163 |
ISSN: |
0006-4971 1528-0020 |
DOI: | 10.1182/blood-2009-11-254078 |
Zusammenfassung: | <jats:title>Abstract</jats:title> <jats:p>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 TCRα/β chains potentially leading to autoimmunity. We hypothesized that a novel single-chain (sc)TCR framework relying on the coexpression of the TCRα constant α (Cα) 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 Cα domain preceded by a TCRα 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/Cα were higher than those of a dcTCR. Antigen-dependent phosphorylation of the proximal effector ζ-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/Cα 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.</jats:p> |
Format: | E-Article |
Quelle: | American Society of Hematology (CrossRef) |
Sprache: | Englisch |