Mimicking an Induced Self Phenotype by Coating Lymphomas with the NKp30 Ligand B7-H6 Promotes NK Cell Cytotoxicity
| Autor: | Jan G. J. van de Winkel, Paul W. H. I. Parren, Daniela Hallack, Christian Kellner, Thomas Valerius, Tina Maurer, Martin Gramatzki, Matthias Peipp, Andreas Humpe, Roland Repp |
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| Rok vydání: | 2012 |
| Předmět: |
B7 Antigens
Lymphoma Immunology Cell Antineoplastic Agents Lymphocyte Activation Cell Degranulation Antibodies Monoclonal Murine-Derived Interleukin 21 Antigens Neoplasm Cell Line Tumor medicine Humans Immunology and Allergy Receptor CD20 Immunity Cellular Natural Cytotoxicity Triggering Receptor 3 biology Receptors IgG Degranulation Drug Synergism Antigens CD20 Cell biology Killer Cells Natural ULBP2 medicine.anatomical_structure Cell culture biology.protein Immunotherapy Rituximab |
| Zdroj: | The Journal of Immunology. 189:5037-5046 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1201321 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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