title: HER2-specific immunoligands engaging NKp30 or NKp80 trigger NK-cell-mediated lysis of tumor cells and enhance antibody-dependent cell-mediated cytotoxicity.
abstract: NK cells detect tumors through activating surface receptors, which bind self-antigens that are frequently expressed upon malignant transformation. To increase the recognition of tumor cells, the extracellular domains of ligands of the activating NK cell receptors NKp30, NKp80 and DNAM-1 (i.e. B7-H6, AICL and PVR, respectively) were fused to a single-chain fragment variable (scFv) targeting the human epidermal growth factor receptor 2 (HER2), which is displayed by various solid tumors. The resulting immunoligands, designated B7-H6:HER2-scFv, AICL:HER2-scFv, and PVR:HER2-scFv, respectively, bound HER2 and the addressed NK cell receptor. However, whereas B7-H6:HER2-scFv and AICL:HER2-scFv triggered NK cells to kill HER2-positive breast cancer cells at nanomolar concentrations, PVR:HER2-scFv was not efficacious. Moreover, NK cell cytotoxicity was enhanced synergistically when B7-H6:HER2-scFv or AICL:HER2-scFv were applied in combination with another HER2-specific immunoligand engaging the stimulatory receptor NKG2D. In contrast, no improvements were achieved by combining B7-H6:HER2-scFv with AICL:HER2-scFv. Additionally, B7-H6:HER2-scFv and AICL:HER2-scFv enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) by the therapeutic antibodies trastuzumab and cetuximab synergistically, with B7-H6:HER2-scFv exhibiting a higher efficacy. In summary, antibody-derived proteins engaging NKp30 or NKp80 may represent attractive biologics to further enhance anti-tumor NK cell responses and may provide an innovative approach to sensitize tumor cells for antibody-based immunotherapy.
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Peipp
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Derer
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lohse
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Staudinger
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Klausz
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Valerius
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Gramatzki
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kellner
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D000920:Antibody-Dependent Cell Cytotoxicity; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology*; D008024:Ligands; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D055607:Receptors, Natural Killer Cell / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D037181:Lectins, C-Type; D008024:Ligands; D055628:Natural Cytotoxicity Triggering Receptor 3; D018719:Erb-b2 Receptor Tyrosine Kinases; D055607:Receptors, Natural Killer Cell; C431711:KLRF1 protein, human; C431710:NCR3 protein, human; C508053:ERBB2 protein, human
keywords: ADCC; B7-H6; NK cells; NKp30; NKp80