TCRs genetically linked to CD28 and CD3ε Do not mispair with endogenous tcr chains and mediate enhanced T cell persistence and anti-melanoma activity

Coen Govers, Zsolt Sebestyén, János Roszik, Mandy Van Brakel, Cor Berrevoets, Árpád Szöor, Konstantina Panoutsopoulou, Marieke Broertjes, Tan Van, György Vereb, János Szöllosi, Reno Debets

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19 Citations (Scopus)

Abstract

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 (i.e., TCR:28ε). 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:28ε depends on the transmembrane domain of CD28, whereas T cell functions depend on the intracellular domains of both CD28 and CD3ε, with IL-2 production showing dependency on CD28:LCK binding. TCR:28ε, 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:28ε does not show signs of off-Target recognition, as evidenced by lack of TCR mispairing, as well as preserved specificity. Notably, when testing TCR:28ε 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.

Original languageEnglish
Pages (from-to)5315-5326
Number of pages12
JournalJournal of Immunology
Volume193
Issue number10
DOIs
Publication statusPublished - Nov 15 2014

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Govers, C., Sebestyén, Z., Roszik, J., Van Brakel, M., Berrevoets, C., Szöor, Á., Panoutsopoulou, K., Broertjes, M., Van, T., Vereb, G., Szöllosi, J., & Debets, R. (2014). TCRs genetically linked to CD28 and CD3ε Do not mispair with endogenous tcr chains and mediate enhanced T cell persistence and anti-melanoma activity. Journal of Immunology, 193(10), 5315-5326. https://doi.org/10.4049/jimmunol.1302074