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, G. Vereb, J. Szöllősi, Reno Debets

Research output: Contribution to journalArticle

16 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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Melanoma
T-Lymphocytes
Transgenes
Synapses
Adoptive Transfer
Genetic Therapy
Interleukin-2
Neoplasms
Cell Survival
Recurrence
Peptides
Genes

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

TCRs genetically linked to CD28 and CD3ε Do not mispair with endogenous tcr chains and mediate enhanced T cell persistence and anti-melanoma activity. / Govers, Coen; Sebestyén, Zsolt; Roszik, János; Van Brakel, Mandy; Berrevoets, Cor; Szöor, Árpád; Panoutsopoulou, Konstantina; Broertjes, Marieke; Van, Tan; Vereb, G.; Szöllősi, J.; Debets, Reno.

In: Journal of Immunology, Vol. 193, No. 10, 15.11.2014, p. 5315-5326.

Research output: Contribution to journalArticle

Govers, C, Sebestyén, Z, Roszik, J, Van Brakel, M, Berrevoets, C, Szöor, Á, Panoutsopoulou, K, Broertjes, M, Van, T, Vereb, G, Szöllősi, 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, vol. 193, no. 10, pp. 5315-5326. https://doi.org/10.4049/jimmunol.1302074
Govers, Coen ; Sebestyén, Zsolt ; Roszik, János ; Van Brakel, Mandy ; Berrevoets, Cor ; Szöor, Árpád ; Panoutsopoulou, Konstantina ; Broertjes, Marieke ; Van, Tan ; Vereb, G. ; Szöllősi, J. ; Debets, Reno. / TCRs genetically linked to CD28 and CD3ε Do not mispair with endogenous tcr chains and mediate enhanced T cell persistence and anti-melanoma activity. In: Journal of Immunology. 2014 ; Vol. 193, No. 10. pp. 5315-5326.
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AU - Roszik, János

AU - Van Brakel, Mandy

AU - Berrevoets, Cor

AU - Szöor, Árpád

AU - Panoutsopoulou, Konstantina

AU - Broertjes, Marieke

AU - Van, Tan

AU - Vereb, G.

AU - Szöllősi, J.

AU - Debets, Reno

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