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de Weerdt, Iris; Hofland, Tom; Lameris, Roeland; Endstra, Sanne; Jongejan, Aldo; Moerland, Perry D.; de Bruin, Renee C.G.; Remmerswaal, Ester B.M.; ten Berge, Ineke J.M.; Liu, Nora; van der Stelt, Mario; Faber, Laura M.; Levin, Mark-David; Eldering, Eric; Tonino, Sanne H.; de Gruijl, Tanja D.; van der Vliet, Hans J.; Kater, Arnon P.
Blood, 11/2018, Letnik: 132, Številka: 21Journal Article
The efficacy of autologous (αβ) T-cell–based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2-T cell subset consists of cytotoxic T lymphocytes with potent antilymphoma activity via a major histocompatibility complex–independent mechanism. We studied whether Vγ9Vδ2-T cells can be exploited as autologous effector lymphocytes in CLL. Healthy control Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and degranulation, despite an increased frequency of the effector-type subset. Consequently, cytotoxicity against malignant B cells was hampered. A comparable dysfunctional phenotype was observed in healthy Vγ9Vδ2-T cells after coculture with CLL cells, indicating a leukemia-induced mechanism. Gene-expression profiling implicated alterations in synapse formation as a conceivable contributor to compromised Vγ9Vδ2-T–cell function in CLL patients. Dysfunction of Vγ9Vδ2-T cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded Vγ9Vδ2-T cells with a memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in Vγ9Vδ2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2-T cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2-T cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-T-cell–based therapy with ibrutinib. •Healthy Vγ9Vδ2-T cells recognize and lyse CLL cells, but CLL-derived Vγ9Vδ2-T cells have impaired cytotoxicity and cytokine production.•Vγ9Vδ2-T–cell dysfunction is reversible upon ex vivo activation with autologous moDCs, and ibrutinib promotes an antitumor TH1 phenotype. Display omitted
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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