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

• DOI: 10.1007/s00262-021-02870-2
• Publication Date: 2021-02-11T15:00:15Z
• Authors: Masanobu Shiga; Jun Miyazaki; Kozaburo Tanuma; Yoshiyuki Nagumo; Takayuki Yoshino; Shuya Kandori; Hiromitsu Negoro; Takahiro Kojima; Ryota Tanaka; Naoko Okiyama; Yasuhiro Fujisawa; Miyuki Watanabe; Sho Yamasaki; Hideyasu Kiyohara; Makoto Watanabe; Taka-aki Sato; Hideaki Tahara; Hiroyuki Nishiyama; Ikuya Yano
• Keywords: 0301 basic medicine; Molecular Structure; Dendritic Cells; CD8-Positive T-Lymphocytes; Chemical Fractionation; Lymphocyte Activation; Mycobacterium bovis; Immunophenotyping; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Antineoplastic Agents, Immunological; Adjuvants, Immunologic; Liposomes; Solvents; Animals; Cord Factors; Cytokines; Humans; Immunologic Factors; Female; Infusions, Parenteral

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.