title: Interleukin-21 enhances NK cell activation in response to antibody-coated targets.
abstract: NK cells express an activating FcR (FcgammaRIIIa) that mediates Ab-dependent cellular cytotoxicity and the production of immune modulatory cytokines in response to Ab-coated targets. IL-21 has antitumor activity in murine models that depends in part on its ability to promote NK cell cytotoxicity and IFN-gamma secretion. We hypothesized that the NK cell response to FcR stimulation would be enhanced by the administration of IL-21. Human NK cells cultured with IL-21 and immobilized IgG or human breast cancer cells coated with a therapeutic mAb (trastuzumab) secreted large amounts of IFN-gamma. Increased secretion of TNF-alpha and the chemokines IL-8, MIP-1alpha, and RANTES was also observed under these conditions. NK cell IFN-gamma production was dependent on distinct signals mediated by the IL-21R and the FcR and was abrogated in STAT1-deficient NK cells. Supernatants derived from NK cells that had been stimulated with IL-21 and mAb-coated breast cancer cells were able to drive the migration of naive and activated T cells in an in vitro chemotaxis assay. IL-21 also enhanced NK cell lytic activity against Ab-coated tumor cells. Coadministration of IL-21 and Ab-coated tumor cells to immunocompetent mice led to synergistic production of IFN-gamma by NK cells. Furthermore, the administration of IL-21 augmented the effects of an anti-HER2/neu mAb in a murine tumor model, an effect that required IFN-gamma. These findings demonstrate that IL-21 significantly enhances the NK cell response to Ab-coated targets and suggest that IL-21 would be an effective adjuvant to administer in combination with therapeutic mAbs.
authors.affiliation: Integrated Biomedical Sciences Graduate Program, Department of Molecular Virology, Arthur G. James Comprehensive Cancer Center and Solove Research Institute, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Roda
authors.forename: Robin
authors.initials: R
authors.lastname: Parihar
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.forename: Aruna
authors.initials: A
authors.lastname: Mani
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D018925:Chemokines / Q000096:biosynthesis / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D007378:Interleukins / Q000008:administration & dosage / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D000068878:Trastuzumab; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000098546:Interleukin-21
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018925:Chemokines; D007074:Immunoglobulin G; D007371:Interferon-gamma; D007378:Interleukins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D014409:Tumor Necrosis Factor-alpha; D000098546:Interleukin-21