Mimicking an induced self phenotype by coating lymphomas with the NKp30 ligand B7-H6 promotes NK cell cytotoxicity.
J Immunol
; 189(10): 5037-46, 2012 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-23066150
ABSTRACT
Induced self expression of the NKp30 ligand B7-H6 facilitates NK cell-mediated elimination of stressed cells. A fusion protein consisting of the ectodomain of B7-H6 and the CD20 single-chain fragment variable 7D8 was generated to mimic an induced self phenotype required for NK cell-mediated target cell elimination. B7-H67D8 had bifunctional properties as reflected by its ability to simultaneously bind to the CD20 Ag and to the NKp30 receptor. B7-H67D8 bound by CD20(+) lymphoma cells activated human NK cells and triggered degranulation. Consequently, the immunoligand B7-H67D8 induced killing of lymphoma-derived cell lines as well as fresh tumor cells from chronic lymphocytic leukemia or lymphoma patients. B7-H67D8 was active at nanomolar concentrations in a strictly Ag-specific manner and required interaction with both CD20 and NKp30. Remarkably, NK cell cytotoxicity was further augmented by concomitant activation of Fcγ receptor IIIa or NK group 2 member D. Thus, B7-H67D8 acted synergistically with the CD20 Ab rituximab and the immunoligand ULBP27D8, which was similarly designed as B7-H67D8 but engaging the NK group 2 member D receptor. In conclusion, to our knowledge, B7-H67D8 represents the first Ab-based molecule stimulating NKp30-mediated NK cell cytotoxicity for therapeutic purposes and provides proof of concept that Ag-specific NKp30 engagement may represent an innovative strategy to enhance antitumoral NK cell cytotoxicity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células Matadoras Naturais
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Ativação Linfocitária
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Degranulação Celular
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Receptor 3 Desencadeador da Citotoxicidade Natural
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Antígenos B7
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Imunidade Celular
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Linfoma
Limite:
Humans
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2012
Tipo de documento:
Article