title: Integrin receptors on tumor cells facilitate NK cell-mediated antibody-dependent cytotoxicity.
abstract: NK cells that mediate ADCC play an important role in tumor-specific immunity. We have examined factors limiting specific lysis of tumor cells by CD16.NK-92 cells induced by CNTO 95LF antibodies recognizing αV integrins that are overexpressed on many tumor cells. Although all tested tumor cells were killed by CD16.NK-92 effectors in the presence of the antibodies, the killing of target cells with a low level of ICAM-1 expression revealed a dramatic decrease in their specific lysis at high antibody concentration, revealing a dose limiting effect. A similar effect was also observed with primary human NK cells. The effect was erased after IFN-γ treatment of tumor cells resulting in upregulation of ICAM-1. Furthermore, killing of the same tumor cells induced by Herceptin antibody was significantly impaired in the presence of CNTO 95Ala-Ala antibody variant that blocks αV integrins but is incapable of binding to CD16. These data suggest that αV integrins on tumor cells could compensate for the loss of ICAM-1 molecules, thereby facilitating ADCC by NK cells. Thus, NK cells could exercise cytolytic activity against ICAM-1 deficient tumor cells in the absence of proinflammatory cytokines, emphasizing the importance of NK cells in tumor-specific immunity at early stages of cancer.
authors.affiliation: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Anikeeva
authors.forename: Maria
authors.initials: M
authors.lastname: Steblyanko
authors.forename: Svetlana
authors.initials: S
authors.lastname: Fayngerts
authors.forename: Natalya
authors.initials: N
authors.lastname: Kopylova
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Marshall
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Powers
authors.forename: Takami
authors.initials: T
authors.lastname: Sato
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Campbell
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sykulev
mesh_terms: D000906:Antibodies / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D058851:GPI-Linked Proteins / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D039564:Integrin alphaV / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D039564:Integrin alphaV; D017452:Receptors, IgG; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; C486839:intetumumab
keywords: ADCC; Adhesion receptors; NK cells; Tumor cells