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Cancer Immunology, Immunotherapy

, Volume 62, Issue 6, pp 1073–1082 | Cite as

Effects of interleukin-18 on natural killer cells: costimulation of activation through Fc receptors for immunoglobulin

  • Shivani Srivastava
  • David Pelloso
  • Hailin Feng
  • Larry Voiles
  • David Lewis
  • Zdenka Haskova
  • Margaret Whitacre
  • Stephen Trulli
  • Yi-Jiun Chen
  • John Toso
  • Zdenka L. Jonak
  • Hua-Chen Chang
  • Michael J. Robertson
Original Article

Abstract

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.

Keywords

Cancer immunotherapy Cytokines Monoclonal antibodies Lymphoma Rituximab 

Notes

Acknowledgments

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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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Shivani Srivastava
    • 1
    • 2
  • David Pelloso
    • 1
    • 2
  • Hailin Feng
    • 1
  • Larry Voiles
    • 3
  • David Lewis
    • 3
  • Zdenka Haskova
    • 4
  • Margaret Whitacre
    • 4
  • Stephen Trulli
    • 4
  • Yi-Jiun Chen
    • 4
  • John Toso
    • 4
  • Zdenka L. Jonak
    • 4
  • Hua-Chen Chang
    • 3
  • Michael J. Robertson
    • 1
    • 2
  1. 1.Bone Marrow and Stem Cell Transplantation ProgramIndianapolisUSA
  2. 2.Lymphoma ProgramIndiana University Medical CenterIndianapolisUSA
  3. 3.Department of BiologyIndiana University-Purdue University School of ScienceIndianapolisUSA
  4. 4.GlaxoSmithKlineKing of PrussiaUSA

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