Kellner, Christian;
Maurer, Tina;
Hallack, Daniela;
Repp, Roland;
van de Winkel, Jan G. J.;
Parren, Paul W. H. I.;
Valerius, Thomas;
Humpe, Andreas;
Gramatzki, Martin;
Peipp, Matthias
Mimicking an Induced Self Phenotype by Coating Lymphomas with the NKp30 Ligand B7-H6 Promotes NK Cell Cytotoxicity
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Media type:
E-Article
Title:
Mimicking an Induced Self Phenotype by Coating Lymphomas with the NKp30 Ligand B7-H6 Promotes NK Cell Cytotoxicity
Contributor:
Kellner, Christian;
Maurer, Tina;
Hallack, Daniela;
Repp, Roland;
van de Winkel, Jan G. J.;
Parren, Paul W. H. I.;
Valerius, Thomas;
Humpe, Andreas;
Gramatzki, Martin;
Peipp, Matthias
imprint:
The American Association of Immunologists, 2012
Description:
<jats:title>Abstract</jats:title>
<jats:p>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-H6:7D8 had bifunctional properties as reflected by its ability to simultaneously bind to the CD20 Ag and to the NKp30 receptor. B7-H6:7D8 bound by CD20+ lymphoma cells activated human NK cells and triggered degranulation. Consequently, the immunoligand B7-H6:7D8 induced killing of lymphoma-derived cell lines as well as fresh tumor cells from chronic lymphocytic leukemia or lymphoma patients. B7-H6:7D8 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-H6:7D8 acted synergistically with the CD20 Ab rituximab and the immunoligand ULBP2:7D8, which was similarly designed as B7-H6:7D8 but engaging the NK group 2 member D receptor. In conclusion, to our knowledge, B7-H6:7D8 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.</jats:p>