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Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1

Nature Immunology volume 13, pages 832–842 (2012)Cite this article

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Abstract

The mechanisms by which tumor microenvironments modulate nucleic acid–mediated innate immunity remain unknown. Here we identify the receptor TIM-3 as key in circumventing the stimulatory effects of nucleic acids in tumor immunity. Tumor-associated dendritic cells (DCs) in mouse tumors and patients with cancer had high expression of TIM-3. DC-derived TIM-3 suppressed innate immune responses through the recognition of nucleic acids by Toll-like receptors and cytosolic sensors via a galectin-9-independent mechanism. In contrast, TIM-3 interacted with the alarmin HMGB1 to interfere with the recruitment of nucleic acids into DC endosomes and attenuated the therapeutic efficacy of DNA vaccination and chemotherapy by diminishing the immunogenicity of nucleic acids released from dying tumor cells. Our findings define a mechanism whereby tumor microenvironments suppress antitumor immunity mediated by nucleic acids.

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Figure 1: Expression of TIM-3 on TADCs.
Figure 2: TIM-3 suppresses innate responses to nucleic acids.
Figure 3: TIM-3 impedes the in vivo antitumor activities of DNA.
Figure 4: Type I interferon and IL-12 mediate anti-TIM-3-mediated antitumor responses.
Figure 5: TIM-3 regulates innate responses by a galectin-9-independent mechanism.
Figure 6: TIM-3 serves as a putative receptor for HMGB1.
Figure 7: TIM-3 inhibits the recruitment of nucleic acids into endosomes.
Figure 8: TIM-3 impedes the antitumor effects of chemotherapy.

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Acknowledgements

We thank M. Bianchi (San Raffaele University) for MEFs deficient in HMGB1 and HMGB2; O. Takeuchi and S. Akira (Osaka University) for mice deficient in both TBK1 and TNF; J. Wolchok (Memorial Sloan-Kettering Cancer Center) for plasmids encoding gp100 and TRP-2; G. Dranoff for comments on the manuscript; and T. Yamashina for assistance with animal care. Supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (H. Yagita and M.J.), the National Cancer Center Research and Development Fund (H.Ya.), the Institute for Genetic Medicine of Hokkaido University (M.J., M.H. and H.Ya.), the Takeda Science Foundation (M.J.), the Sumitomo Foundation (M.J.), Terumo Life Science Foundation (M.J.), Senshin Medical Research Foundation (M.J.) and Japan Leukemia Research Foundation (M.J.).

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Authors and Affiliations

  1. Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

    Shigeki Chiba, Muhammad Baghdadi, Hironori Yoshiyama & Masahisa Jinushi

  2. Division of Signaling on Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

    Akinori Takaoka

  3. Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Ichiro Kinoshita & Hirotoshi Dosaka-Akita

  4. Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

    Hisaya Akiba & Hideo Yagita

  5. Department of Pathophysiology and Signal Transduction, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Yoichiro Fujioka & Yusuke Ohba

  6. Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA

    Jacob V Gorman & John D Colgan

  7. Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Mitsuomi Hirashima

  8. Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

    Toshimitsu Uede

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  1. Shigeki Chiba
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Contributions

M.J. and H.Ya. designed the experiments; S.C., M.B., H.A., H.Yo., Y.F. and M.J. prepared reagents and did the experiments; S.C., M.B., H.A., H.Yo., Y.F., Y.O., J.D.C., M.H., T.U., A.T., H.Ya. and M.J. analyzed and discussed the data; I.K. and H.D.-A. provided clinical samples; H.A., J.V.G., J.D.C., M.H. and H.Ya. developed new materials; and M.J. was responsible for the overall study design and writing the manuscript.

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Correspondence to Masahisa Jinushi.

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Chiba, S., Baghdadi, M., Akiba, H. et al. Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol 13, 832–842 (2012). https://doi.org/10.1038/ni.2376

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