Efficient lysis of rhabdomyosarcoma cells by cytokine-induced killer cells : implications for adoptive immunotherapy after allogeneic stem cell transplantation

Background: Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood and has a poor prognosis. Here we assessed the capability of ex vivo expanded cytokine-induced killer cells to lyse both alveolar and embry
Background: Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood and has a poor prognosis. Here we assessed the capability of ex vivo expanded cytokine-induced killer cells to lyse both alveolar and embryonic rhabdomyosarcoma cell lines and investigated the mechanisms involved.

Design and Methods: Peripheral blood mononuclear cells from six healthy donors were used to generate and expand cytokine-induced killer cells. The phenotype and composition of these cells were determined by multiparameter flow cytometry, while their cytotoxic effect against rhabdomyosarcoma cells was evaluated by a europium release assay.

Results: Cytokine-induced killer cells efficiently lysed cells from both rhabdomyosarcoma cell lines. Antibody-mediated masking of either NKG2D molecule on cytokine-induced killer cells or its ligands on rhabdomyosarcoma cells (major histocompatibility antigen related chain A and B and UL16 binding protein 2) diminished this effect by 50%, suggesting a major role for the NKG2D molecule in rhabdomyosarcoma cell killing. No effect was observed after blocking CD11a, CD3 or TCRαβ molecules on cytokine-induced killer cells or CD1d on rhabdomyosar-coma cells. Remarkably, cytokine-induced killer cells used tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to activate caspase-3, as the main caspase responsible for the execution of apoptosis. Accordingly, blocking TRAIL receptors on embryonic rhabdomyosarcoma cell lines significantly reduced the anti-tumor effect of cytokine-induced killer cells. About 50% of T cells within the cytokine-induced killer population had an effector memory phenotype, 20% had a naïve phenotype and approximately 30% of the cells had a central memory phenotype. In addition, cytokine-induced killer cells expressed low levels of activation-induced markers CD69 and CD137 and demonstrated a low alloreactive potential.

Conclusions: Our data suggest that cytokine-induced killer cells may be used as a novel adoptive immunotherapy for the treatment of patients with rhabdomyosarcoma after allogeneic stem cell transplantation.
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Metadaten
Author:Selim Kuçi, Eva Rettinger, Bernhard Voß, Gerrit Weber, Miriam Stais, Hermann Kreyenberg, Andre Willasch, Zyrafete Kuçi, Ewa Koscielniak, Stephan Klöss, Dorothee von Laer, Thomas Klingebiel, Peter Bader
URN:urn:nbn:de:hebis:30:3-266005
DOI:http://dx.doi.org/10.3324/haematol.2009.019885
ISSN:1592-8721
ISSN:0390-6078
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=20378565
Parent Title (English):Haematologica
Publisher:Ferrata Storti Foundation
Place of publication:Pavia
Document Type:Article
Language:English
Date of Publication (online):2010/04/07
Date of first Publication:2010/04/07
Publishing Institution:Univ.-Bibliothek Frankfurt am Main
Release Date:2012/11/13
Volume:95
Issue:9
Pagenumber:8
First Page:1579
Last Page:1586
HeBIS PPN:358233682
Institutes:Medizin
Georg-Speyer-Haus
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License Logo Veröffentlichungsvertrag für Publikationen

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