V{gamma}9V{delta}2 T Lymphocytes EfficientlyRecognize and Kill Zoledronate-Sensitized, Imatinib-Sensitive, andImatinib-Resistant Chronic Myelogenous Leukemia Cells.

Diana Di Liberto, Carmela La Mendola, Alfredo Salerno, Francesco Dieli, Nadia Rosalia Caccamo, Giorgio Stassi, Giuliana Guggino, Matilde Todaro, Serena Meraviglia, Paolo Vigneri, Jean Fourniè, Francesco Di Raimondo, Angelo Messina, Marisa Spina, Valentina Orlando

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Abstract

Imatinib mesylate (imatinib), a competitive inhibitor of the BCR-ABL tyrosine kinase, is highly effective against chronic myelogenous leukemia (CML) cells. However, because 20-30% of patients affected by CML display either primary or secondary resistance to imatinib, intentional activation of Vγ9Vδ2 T cells by phosphoantigens or by agents that cause their accumulation within cells, such as zoledronate, may represent a promising strategy for the design of a novel and highly innovative immunotherapy capable to overcome imatinib resistance. In this study, we show that Vγ9Vδ2 T lymphocytes recognize, trogocytose, and efficiently kill imatinib-sensitive and -resistant CML cell lines pretreated with zoledronate. Vγ9Vδ2 T cell cytotoxicity was largely dependent on the granule exocytosis- and partly on TRAIL-mediated pathways, was TCR-mediated, and required isoprenoid biosynthesis by zoledronate-treated CML cells. Importantly, Vγ9Vδ2 T cells from patients with CML can be induced by zoledronate to develop antitumor activity against autologous and allogeneic zoledronate-treated leukemia cells, both in vitro and when transferred into immunodeficient mice in vivo. We conclude that intentional activation of Vγ9Vδ2 T cells by zoledronate may substantially increase their antileukemia activities and represent a novel strategy for CML immunotherapy.
Lingua originaleEnglish
pagine (da-a)3260-3268
Numero di pagine9
RivistaJournal of Immunology
Volume184
Stato di pubblicazionePublished - 2010

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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