Journal
JOURNAL OF IMMUNOLOGY
Volume 193, Issue 10, Pages 5315-5326Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1302074
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Funding
- European Union 6th Framework Adoptive Engineered T cell Targeting to Activate Cancer Killing (ATTACK) [018914]
- National Science Foundation Theoretical Atomic, Molecular, and Optical Physics [TAMOP 4.2.1/B-09/1/KONV-2010-0007, TAMOP 4.22/B-10/1/2010-0024, TAMOP 4.2.2/A-11/1/KONV-20120025]
- Hungarian Scientific Research Fund [OTKA NK 101337]
- Baross Gabor Program [REG_EA09-12009-0010]
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Adoptive transfer of T cells that are gene engineered to express a defined TCR represents a feasible and promising therapy for patients with tumors. However, TCR gene therapy is hindered by the transient presence and effectiveness of transferred T cells, which are anticipated to be improved by adequate T cell costimulation. In this article, we report the identification and characterization of a novel two-chain TCR linked to CD28 and CD3 epsilon (i.e., TCR:28 epsilon. This modified TCR demonstrates enhanced binding of peptide-MHC and mediates enhanced T cell function following stimulation with peptide compared with wild-type TCR. Surface expression of TCR 28 epsilon depends on the transmembrane domain of CD28, whereas T cell functions depend on the intracellular domains of both CD28 and CD3 epsilon, with IL-2 production showing dependency on CD28: LCK binding. TCR:28 epsilon, but not wild-type TCR, induces detectable immune synapses in primary human T cells, and such immune synapses show significantly enhanced accumulation of TCR transgenes and markers of early TCR signaling, such as phosphorylated LCK and ERK. Importantly, TCR:28 epsilon does not show signs of off-target recognition, as evidenced by lack of TCR mispairing, as well as preserved specificity. Notably, when testing TCR:28 epsilon in immune-competent mice, we observed a drastic increase in T cell survival, which was accompanied by regression of large melanomas with limited recurrence. Our data argue that TCR transgenes that contain CD28, and, thereby, may provide T cell costimulation in an immune-suppressive environment, represent candidate receptors to treat patients with tumors.
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