Article: article from journal or magazin.
Coexpression of the T-cell receptor constant alpha domain triggers tumor reactivity of single-chain TCR-transduced human T cells.
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.
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
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