BACKGROUND: Natural killer cell cytotoxicity is decreased in patients with acute myeloid leukemia in comparison to that in normal controls. Tumor-derived microvesicles present in patients' sera exert detrimental effects on immune cells and may influence tumor progression. DESIGN AND METHODS: We investigated the microvesicle protein level, molecular profile and suppression of natural killer cell activity in patients with newly diagnosed acute myeloid leukemia. RESULTS: The patients' sera contained higher levels of microvesicles compared to the levels in controls (P<0.001). Isolated microvesicles had a distinct molecular profile: in addition to conventional microvesicle markers, they contained membrane-associated transforming growth factor-β1, MICA/MICB and myeloid blasts markers, CD34, CD33 and CD117. These microvesicles decreased natural killer cell cytotoxicity (P<0.002) and down-regulated expression of NKG2D in normal natural killer cells (P<0.001). Sera from patients with acute myeloid leukemia contained elevated levels of transforming growth factor-β, and urea-mediated dissociation of microvesicles further increased the levels of this protein. Neutralizing anti-transforming growth factor-β1 antibodies inhibited microvesicle-mediated suppression of natural killer cell activity and NKG2D down-regulation. Interleukin-15 protected natural killer cells from adverse effects of tumor-derived microvesicles. CONCLUSIONS: We provide evidence for the existence in acute myeloid leukemia of a novel mechanism of natural killer cell suppression mediated by tumor-derived microvesicles and for the ability of interleukin-15 to counteract this suppression.
BACKGROUND: Natural killer cell cytotoxicity is decreased in patients with acute myeloid leukemia in comparison to that in normal controls. Tumor-derived microvesicles present in patients' sera exert detrimental effects on immune cells and may influence tumor progression. DESIGN AND METHODS: We investigated the microvesicle protein level, molecular profile and suppression of natural killer cell activity in patients with newly diagnosed acute myeloid leukemia. RESULTS: The patients' sera contained higher levels of microvesicles compared to the levels in controls (P<0.001). Isolated microvesicles had a distinct molecular profile: in addition to conventional microvesicle markers, they contained membrane-associated transforming growth factor-β1, MICA/MICB and myeloid blasts markers, CD34, CD33 and CD117. These microvesicles decreased natural killer cell cytotoxicity (P<0.002) and down-regulated expression of NKG2D in normal natural killer cells (P<0.001). Sera from patients with acute myeloid leukemia contained elevated levels of transforming growth factor-β, and urea-mediated dissociation of microvesicles further increased the levels of this protein. Neutralizing anti-transforming growth factor-β1 antibodies inhibited microvesicle-mediated suppression of natural killer cell activity and NKG2D down-regulation. Interleukin-15 protected natural killer cells from adverse effects of tumor-derived microvesicles. CONCLUSIONS: We provide evidence for the existence in acute myeloid leukemia of a novel mechanism of natural killer cell suppression mediated by tumor-derived microvesicles and for the ability of interleukin-15 to counteract this suppression.
Authors: Michael Boyiadzis; Sarfraz Memon; Jesse Carson; Kenton Allen; Miroslaw J Szczepanski; Barbara A Vance; Robert Dean; Michael R Bishop; Ronald E Gress; Frances T Hakim Journal: Biol Blood Marrow Transplant Date: 2008-03 Impact factor: 5.742
Authors: Thomas Ranson; Christian A J Vosshenrich; Erwan Corcuff; Odile Richard; Werner Müller; James P Di Santo Journal: Blood Date: 2003-02-13 Impact factor: 22.113
Authors: Jeong Whun Kim; Eva Wieckowski; Douglas D Taylor; Torsten E Reichert; Simon Watkins; Theresa L Whiteside Journal: Clin Cancer Res Date: 2005-02-01 Impact factor: 12.531
Authors: Bérengère Salomé; Alejandra Gomez-Cadena; Romain Loyon; Madeleine Suffiotti; Valentina Salvestrini; Tania Wyss; Giulia Vanoni; Dan Fu Ruan; Marianna Rossi; Alessandra Tozzo; Paolo Tentorio; Elena Bruni; Carsten Riether; Eva-Maria Jacobsen; Peter Jandus; Curdin Conrad; Manfred Hoenig; Ansgar Schulz; Katarzyna Michaud; Matteo Giovanni Della Porta; Silvia Salvatore; Ping-Chih Ho; David Gfeller; Adrian Ochsenbein; Domenico Mavilio; Antonio Curti; Emanuela Marcenaro; Alexander Steinle; Amir Horowitz; Pedro Romero; Sara Trabanelli; Camilla Jandus Journal: Blood Adv Date: 2019-11-26
Authors: B Schilling; E S Halstead; P Schuler; M Harasymczuk; J E Egan; T L Whiteside Journal: Cancer Immunol Immunother Date: 2012-01-20 Impact factor: 6.968
Authors: Marta Szajnik; Magdalena Derbis; Michal Lach; Paulina Patalas; Marcin Michalak; Hanna Drzewiecka; Dariusz Szpurek; Andrzej Nowakowski; Marek Spaczynski; Włodzimierz Baranowski; Theresa L Whiteside Journal: Gynecol Obstet (Sunnyvale) Date: 2013-04-29