Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses

  1. Shiho Chiba
  2. Hiroaki Ikushima
  3. Hiroshi Ueki
  4. Hideyuki Yanai
  5. Yoshitaka Kimura
  6. Sho Hangai
  7. Junko Nishio
  8. Hideo Negishi
  9. Tomohiko Tamura
  10. Shinobu Saijo
  11. Yoichiro Iwakura
  12. Tadatsugu Taniguchi  Is a corresponding author
  1. Institute of Industrial Science, The University of Tokyo, Japan
  2. Yokohama City University Graduate School of Medicine, Japan
  3. Medical Mycology Research Center, Chiba University, Japan
  4. Research Institute for Biomedical Sciences, Tokyo University of Science, Japan

Abstract

The eradication of tumor cells requires communication to and signaling by cells of the immune system. Natural killer (NK) cells are essential tumor-killing effector cells of the innate immune system; however, little is known about whether or how other immune cells recognize tumor cells to assist NK cells. Here, we show that the innate immune receptor Dectin-1 expressed on dendritic cells and macrophages is critical to NK-mediated killing of tumor cells that express N-glycan structures at high levels. Receptor recognition of these tumor cells causes the activation of the IRF5 transcription factor and downstream gene induction for the full-blown tumoricidal activity of NK cells. Consistent with this, we show exacerbated in vivo tumor growth in mice genetically deficient in either Dectin-1 or IRF5. The critical contribution of Dectin-1 in the recognition of and signaling by tumor cells may offer new insight into the anti-tumor immune system with therapeutic implications.

Article and author information

Author details

  1. Shiho Chiba

    Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
    Competing interests
    No competing interests declared.
  2. Hiroaki Ikushima

    Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
    Competing interests
    No competing interests declared.
  3. Hiroshi Ueki

    Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
    Competing interests
    No competing interests declared.
  4. Hideyuki Yanai

    Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
    Competing interests
    No competing interests declared.
  5. Yoshitaka Kimura

    Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
    Competing interests
    No competing interests declared.
  6. Sho Hangai

    Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
    Competing interests
    No competing interests declared.
  7. Junko Nishio

    Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
    Competing interests
    No competing interests declared.
  8. Hideo Negishi

    Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
    Competing interests
    No competing interests declared.
  9. Tomohiko Tamura

    Yokohama City University Graduate School of Medicine, Yokohama, Japan
    Competing interests
    No competing interests declared.
  10. Shinobu Saijo

    Medical Mycology Research Center, Chiba University, Chiba, Japan
    Competing interests
    No competing interests declared.
  11. Yoichiro Iwakura

    Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan
    Competing interests
    No competing interests declared.
  12. Tadatsugu Taniguchi

    Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
    For correspondence
    tada@m.u-tokyo.ac.jp
    Competing interests
    Tadatsugu Taniguchi, Senior editor, eLife.

Ethics

Animal experimentation: All animal care and experiments conformed to the guidelines for animal experiments of the University of Tokyo, and were approved by the animal research committee of the University of Tokyo (Reference number: P10-122 and P10-123).

Copyright

© 2014, Chiba et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 6,352
    views
  • 1,034
    downloads
  • 155
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Shiho Chiba
  2. Hiroaki Ikushima
  3. Hiroshi Ueki
  4. Hideyuki Yanai
  5. Yoshitaka Kimura
  6. Sho Hangai
  7. Junko Nishio
  8. Hideo Negishi
  9. Tomohiko Tamura
  10. Shinobu Saijo
  11. Yoichiro Iwakura
  12. Tadatsugu Taniguchi
(2014)
Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses
eLife 3:e04177.
https://doi.org/10.7554/eLife.04177

Share this article

https://doi.org/10.7554/eLife.04177

Further reading

    1. Immunology and Inflammation
    Josep Garnica, Patricia Sole ... Pere Santamaria
    Research Article

    Chronic antigenic stimulation can trigger the formation of interleukin 10 (IL-10)-producing T-regulatory type 1 (TR1) cells in vivo. We have recently shown that murine T-follicular helper (TFH) cells are precursors of TR1 cells and that the TFH-to-TR1 cell transdifferentiation process is characterized by the progressive loss and acquisition of opposing transcription factor gene expression programs that evolve through at least one transitional cell stage. Here, we use a broad range of bulk and single-cell transcriptional and epigenetic tools to investigate the epigenetic underpinnings of this process. At the single-cell level, the TFH-to-TR1 cell transition is accompanied by both, downregulation of TFH cell-specific gene expression due to loss of chromatin accessibility, and upregulation of TR1 cell-specific genes linked to chromatin regions that remain accessible throughout the transdifferentiation process, with minimal generation of new open chromatin regions. By interrogating the epigenetic status of accessible TR1 genes on purified TFH and conventional T-cells, we find that most of these genes, including Il10, are already poised for expression at the TFH cell stage. Whereas these genes are closed and hypermethylated in Tconv cells, they are accessible, hypomethylated, and enriched for H3K27ac-marked and hypomethylated active enhancers in TFH cells. These enhancers are enriched for binding sites for the TFH and TR1-associated transcription factors TOX-2, IRF4, and c-MAF. Together, these data suggest that the TR1 gene expression program is genetically imprinted at the TFH cell stage.

    1. Genetics and Genomics
    2. Immunology and Inflammation
    Stephanie Guillet, Tomi Lazarov ... Frédéric Geissmann
    Research Article

    Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients’ ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.