Anti-tumor immunity via the superoxide-eosinophil axis induced by a lipophilic component of Mycobacterium lipomannan

• Published in: International immunology Vol. 29; no. 9; pp. 411 - 421
• Main Authors: Ito, Toshihiro, Hirahara, Kiyoshi, Onodera, Atsushi, Koyama-Nasu, Ryo, Yano, Ikuya, Nakayama, Toshinori
• Format: Journal Article
• Language: English
• Published: England 01.11.2017
• Subjects: Animals; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Wall - immunology; Chemokine CCL5 - metabolism; Cytotoxicity, Immunologic; Dendritic Cells - immunology; Eosinophils - immunology; Female; Immunologic Memory; Immunotherapy, Adoptive - methods; Lipopolysaccharides - immunology; Mice; Mice, Inbred BALB C; Mycobacterium bovis - immunology; Neoplasms, Experimental - immunology; Neoplasms, Experimental - therapy; Superoxides - metabolism; Th2 Cells - immunology; Transcriptome; Tumor Burden; Tumor Microenvironment; BCG-LM; memory Th2 cells; eosinophils; superoxide; CCL5
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxx051

Mycobacterium bovis Bacille Calmette-Guérin (BCG) has been shown to possess potent anti-tumor activity particularly in various animal models, while the cellular and molecular mechanisms underlying its activity are not well understood. We found that lipomannan (BCG-LM), a lipophilic component of the mycobacterial cell envelope, specifically inhibits tumor growth and induces the infiltration of eosinophils at local tumor invasion sites. In contrast, neither lipoarabinomannan (BCG-LAM) nor the cell wall of Mycobacterium bovis BCG (BCG-CW) exerted anti-tumor immunity. BCG-LM enhances cytotoxic activity of eosinophils via the increased production of superoxide. Global transcriptomic analyses of BCG-LM-pulsed dendritic cells identified C-C motif ligand (CCL) 5 as a crucial chemokine for the anti-tumor immunity induced by BCG-LM, indicating that CCL5 plays an important role for the accumulation of eosinophils in the tumor microenvironment. Furthermore, BCG-LM and memory Th2 cells exerted a synergetic effect on tumor progression by cooperatively enhancing the eosinophil function. Thus, this study revealed an un-identified BCG-LM-mediated anti-tumor mechanism via superoxide produced by infiltrated eosinophils in the tumor microenvironment. Since BCG-LM activates this unique pathway, it may have potent therapeutic potential as immune cell therapy for cancer patients.