V gamma 9V delta 2 T lymphocytes efficiently recognize and kill zoledronate-sensitized, imatinib-sensitive, and imatinib-resistant chronic myelogenous leukemia cells.
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 Vgamma9Vdelta2 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 Vgamma9Vdelta2 T lymphocytes recognize, trogocytose, and efficiently kill imatinib-sensitive and -resistant CML cell lines pretreated with zoledronate. Vgamma9Vdelta2 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, Vgamma9Vdelta2 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 Vgamma9Vdelta2 T cells by zoledronate may substantially increase their antileukemia activities and represent a novel strategy for CML immunotherapy.
Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Palermo, Italy.
Matilde
M
D'Asaro
Carmela
C
La Mendola
Diana
D
Di Liberto
Valentina
V
Orlando
Matilde
M
Todaro
Marisa
M
Spina
Giuliana
G
Guggino
Serena
S
Meraviglia
Nadia
N
Caccamo
Angelo
A
Messina
Alfredo
A
Salerno
Francesco
F
Di Raimondo
Paolo
P
Vigneri
Giorgio
G
Stassi
Jean Jacques
JJ
Fourniè
Francesco
F
Dieli
D000328:Adult; D000818:Animals; D001549:Benzamides; D002478:Cells, Cultured; D018920:Coculture Techniques; D004164:Diphosphonates / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000276:immunology*; D019008:Drug Resistance, Neoplasm / Q000276:immunology*; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000494:pharmacology*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000077211:Zoledronic Acid
D001549:Benzamides; D004164:Diphosphonates; D007093:Imidazoles; D010879:Piperazines; D011743:Pyrimidines; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; D000077211:Zoledronic Acid; D000068877:Imatinib Mesylate