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The liposome of trehalose dimycolate extracted from M. bovis BCG induces antitumor immunity via the activation of dendritic cells and CD8+ T cells

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Abstract

Intravesical Bovis bacillus Calmette-Guérin (BCG) therapy is the most effective immunotherapy for bladder cancer, but it sometime causes serious side effects because of its inclusion of live bacteria. It is necessary to develop a more active but less toxic immunotherapeutic agent. Trehalose 6,6′-dimycolate (TDM), the most abundant hydrophobic glycolipid of the BCG cell wall, has been reported to show various immunostimulatory activities such as granulomagenesis and adjuvant activity. Here, we developed cationic liposomes incorporating TDM purified from Mycobacterium bovis BCG Connaught, and we investigated the antitumor effect of the cationic liposome TDM (Lip-TDM). Lip-TDM exerted an antitumor effect in bladder cancer, colon cancer, and melanoma-bearing mouse models that was comparable or even superior to that of BCG, with no body weight loss or granuloma formation. The antitumor effect of Lip-TDM disappeared in two types of mice: those with depletion of CD8+ T cells, and those with knockout of macrophage-inducible C-type lectin (Mincle) which recognize TDM. Lip-TDM treatment enhanced the maturation and migration of dendritic cells in the tumor microenvironment in a Mincle-dependent manner. Our results elucidate mechanisms that underlie Lip-TDM treatment and suggest that Lip-TDM has potential as a safe and effective treatment for various cancers.

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Acknowledgements

This work was supported by a grant from the Japan Society for the Promotion of Science KAKENHI, no. 18H02934.

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Authors and Affiliations

  1. Department of Urology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

    Masanobu Shiga, Kozaburo Tanuma, Yoshiyuki Nagumo, Takayuki Yoshino, Shuya Kandori, Hiromitsu Negoro, Takahiro Kojima & Hiroyuki Nishiyama

  2. Department of Urology, School of Medicine, International University of Health and Welfare, 852 Hatakeda, Narita, Chiba, 286-0124, Japan

    Jun Miyazaki

  3. Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

    Ryota Tanaka, Naoko Okiyama & Yasuhiro Fujisawa

  4. Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan

    Miyuki Watanabe & Sho Yamasaki

  5. Laboratory of Molecular Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka, Japan

    Sho Yamasaki

  6. Division of Molecular Design, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka, Japan

    Sho Yamasaki

  7. Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chuo-ku, Chiba, Japan

    Sho Yamasaki

  8. Japan BCG Laboratory, Kiyose, Tokyo, Japan

    Hideyasu Kiyohara

  9. Life Science Research Center, Technology Research Laboratory, Shimadzu, Kyoto, Japan

    Makoto Watanabe & Taka-aki Sato

  10. Project Division of Cancer Biomolecular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Hideaki Tahara

  11. Department of Cancer Drug Discovery and Development, Osaka International Cancer Center, Osaka, Japan

    Hideaki Tahara

  12. Osaka City University, Osaka, Japan

    Ikuya Yano

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  1. Masanobu Shiga
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  2. Jun Miyazaki
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Contributions

JM, HNi, and IY contributed to the study's conception and design. MS, KT, YN, TY, RT, MiW, HK, and MaW performed the experiments. MS, YN, SK, HNe, and TK contributed to the analysis and interpretation of the data. NO, YF, SY, TS, and HT contributed administrative, technical, or material support. MS wrote the first draft of the manuscript. YN, SK, HNe, NO, YF, MiW, and SY critically reviewed and revised the manuscript. JM, TK, HNi, and IY supervised the study. All authors have read and approved the final version of the manuscript.

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Correspondence to Jun Miyazaki.

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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All animal care and experimental procedures were performed in accordance with national and regional legislation on animal protection, and all animal procedures were consistent with the University of Tsukuba's Regulation of Animal Experiments and were approved by the Animal Experiment Committee, University of Tsukuba.

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Shiga, M., Miyazaki, J., Tanuma, K. et al. The liposome of trehalose dimycolate extracted from M. bovis BCG induces antitumor immunity via the activation of dendritic cells and CD8+ T cells. Cancer Immunol Immunother 70, 2529–2543 (2021). https://doi.org/10.1007/s00262-021-02870-2

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