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A CHIMERIC RECEPTOR WITH NKG2D SPECIFICITY ENHANCES NATURAL KILLER CELL ACTIVATION AND KILLING OF TUMOR CELLS.
MedLine Citation:
PMID:  23302231     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Natural killer (NK) cells rely on surface receptors to distinguish healthy cells from cancer cells. We designed a receptor termed NKG2D-DAP10-CD3ζ that is composed of the NK cell activating molecule NKG2D plus two key signaling molecules, DAP10 and CD3ζ, and evaluated its capacity to promote cancer cell killing. Retroviral transduction of NKG2D-DAP10-CD3ζ markedly increased NKG2D surface expression in NK cells, which became consistently more cytotoxic than mock-transduced cells against leukemia and solid tumor cell lines. In contrast, there was no increase in cytotoxicity against non-transformed blood and mesenchymal cells. NKG2D blockade abrogated gains in cytotoxicity to cancer cells. Receptor stimulation triggered signal transduction, secretion of IFNγ, GM-CSF, IL-13, MIP-1α, MIP-1β, CCL5 and TNFα, and massive release of cytotoxic granules which persisted after 48 hours of continuous stimulation. NKG2D-DAP10-CD3ζ-expressing NK cells had considerable anti-tumor activity in a mouse model of osteosarcoma, whereas activated NK cells were ineffective. Thus, the cytotoxic potential of NK cells against a wide spectrum of tumor subtypes could be markedly enhanced by expression of NKG2D-DAP10-CD3ζ receptors. The development of an electroporation method that permits rapid expression of the receptor in a large number of human NK cells facilitates clinical translation of this NK-based strategy for a generalized cellular therapy that may be useful to treat a wide range of cancers.
Authors:
Yu-Hsiang Chang; John Connolly; Noriko Shimasaki; Kousaku Mimura; Koji Kono; Dario Campana
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-10
Journal Detail:
Title:  Cancer research     Volume:  -     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Pediatrics, National University of Singapore.
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