Mimicking an induced self phenotype by coating lymphomas with the NKp30 ligand B7-H6 promotes NK cell cytotoxicity.
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.
Division of Stem Cell Transplantation and Immunotherapy, Department of Medicine II, Christian Albrechts University Kiel, 24105 Kiel, Germany.
Christian
C
Kellner
Tina
T
Maurer
Daniela
D
Hallack
Roland
R
Repp
Jan G J
JG
van de Winkel
Paul W H I
PW
Parren
Thomas
T
Valerius
Andreas
A
Humpe
Martin
M
Gramatzki
Matthias
M
Peipp
D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology; D018951:Antigens, CD20 / Q000235:genetics / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology; D060887:B7 Antigens / Q000819:agonists / Q000235:genetics / Q000494:pharmacology*; D015550:Cell Degranulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects* / Q000235:genetics; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000235:genetics; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG; D000069283:Rituximab
D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D060887:B7 Antigens; C496124:FCGR3A protein, human; C431710:NCR3 protein, human; C542363:NCR3LG1 protein, human; D055628:Natural Cytotoxicity Triggering Receptor 3; D017452:Receptors, IgG; D000069283:Rituximab