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Natural Killer Cells Produce T Cell–Recruiting Chemokines in Response to Antibody-Coated Tumor Cells

¹ Integrated Biomedical Sciences Graduate Program, Departments of ² Molecular Virology, Immunology, and Medical Genetics, ³ Pathology, ⁴ Internal Medicine, and ⁵ Surgery, The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, Ohio

Requests for reprints: William E. Carson, III, Department of Surgery, The Ohio State University, N924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-6306; Fax: 614-688-4366; E-mail: william.carson{at}osumc.edu.

In the current report, we have examined the ability of natural killer (NK) cells to produce T cell–recruiting chemokines following dual stimulation with interleukin (IL)-2 or IL-12 and human breast cancer cells coated with an antitumor antibody (trastuzumab). NK cells stimulated in this manner secreted an array of T cell–recruiting chemotactic factors, including IL-8, macrophage-derived chemokine, macrophage inflammatory protein 1 (MIP-1), monocyte chemoattractant protein 1, and regulated on activation, normal T-cell expressed and secreted (RANTES), whereas stimulation of NK cells with either agent alone had minimal effect. Furthermore, these factors were functional for T-cell chemotaxis as culture supernatants derived from costimulated NK cells induced migration of both naïve and activated T cells in an in vitro chemotaxis assay. T-cell migration was significantly reduced when neutralizing antibodies to IL-8, MIP-1, or RANTES were added to culture supernatants before their use in the chemotaxis assay. In addition, coadministration of trastuzumab-coated tumor cells and IL-12 to mice led to enhanced serum MIP-1. As a clinical correlate, we examined the chemokine content of serum samples from breast cancer patients enrolled on a phase I trial of trastuzumab and IL-12, and found elevated levels of IL-8, RANTES, IFN- inducible protein 10, monokine induced by IFN-, and MIP-1, specifically in those patients that experienced a clinical benefit. Sera from these patients exhibited the ability to direct T-cell migration in a chemotaxis assay, and neutralization of chemokines abrogated this effect. These data are the first to show chemokine production by NK cells, specifically in response to stimulation with antibody-coated tumor cells, and suggest a potential role for NK cell–derived chemokines in patients receiving therapeutic monoclonal antibodies. (Cancer Res 2006; 66(1): 517-26)

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