Effects of interleukin-18 on natural killer cells: costimulation of activation through Fc receptors for immunoglobulin
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The antitumor activity of monoclonal antibodies is mediated by effector cells, such as natural killer (NK) cells, that express Fc receptors for immunoglobulin. Efficacy of monoclonal antibodies, including the CD20 antibody rituximab, could be improved by agents that augment the function of NK cells. Interleukin (IL)-18 is an immunostimulatory cytokine that has antitumor activity in preclinical models. The effects of IL-18 on NK cell function mediated through Fcγ receptors were examined. Human NK cells stimulated with immobilized IgG in vitro secreted IFN-γ as expected; such IFN-γ production was partially inhibited by blocking CD16 with monoclonal antibodies. IL-18 augmented IFN-γ production by NK cells stimulated with immobilized IgG or CD16 antibodies. NK cell IFN-γ production in response to immobilized IgG and/or IL-18 was inhibited by chemical inhibitors of Syk and several other kinases involved in CD16 signaling pathways. IL-18 augmented antibody-dependent cellular cytotoxicity (ADCC) of human NK cells against rituximab-coated Raji cells in vitro. IL-18 and rituximab acted synergistically to promote regression of human lymphoma xenografts in SCID mice. Inasmuch as IL-18 costimulates IFN-γ production and ADCC of NK cells activated through Fc receptors in vitro and augments antitumor activity of rituximab in vivo, it is an attractive cytokine to combine with monoclonal antibodies for treatment of human cancer.
KeywordsCancer immunotherapy Cytokines Monoclonal antibodies Lymphoma Rituximab
This work was supported in part by National Institutes of Health Grant RO1 CA118118 (Michael J. Robertson), Walther Scholar Grant (Shivani Srivastava) from the Indiana University Simon Cancer Center (P30 CA82709) and American Cancer Society IRG (Hua-Chen Chang and Shivani Srivastava). The authors thank Menggang Yu, Ph.D. and Sandra Althouse for statistical support and Lisa Wood, R. N. and nurses in the Indiana CTSI Clinical Research Center for assistance in collection of patient samples.
Conflict of interest
Zdenka Haskova, Margaret Whitacre, Stephen Trulli, Yi-Jiun Chen, John Toso, Zdenka L. Jonak are employees and shareholders of GlaxoSmithKline. All other authors declare that they have no conflict of interest.
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