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* 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;
Immunology and Medical Genetics, Arthur G. James Comprehensive Cancer Center and Solove Research Institute, Ohio State University, Columbus, OH 43210;
Center for Biostatistics, Arthur G. James Comprehensive Cancer Center and Solove Research Institute, Ohio State University, Columbus, OH 43210;
Department of Hematology and Oncology, Arthur G. James Comprehensive Cancer Center and Solove Research Institute, Ohio State University, Columbus, OH 43210;
¶ Department of Internal Medicine, Arthur G. James Comprehensive Cancer Center and Solove Research Institute, Ohio State University, Columbus, OH 43210; and
|| Department of Surgery, Arthur G. James Comprehensive Cancer Center and Solove Research Institute, Ohio State University, Columbus, OH 43210
NK cells express an activating FcR (Fc
RIIIa) 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- 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-. Increased secretion of TNF-
and the chemokines IL-8, MIP-1, and RANTES was also observed under these conditions. NK cell IFN- 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- 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-. 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.
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