Immunotherapy of Bacillus Calmette‑Guérin by targeting macrophages against bladder cancer in a NOD/scid IL2Rg‑/‑ mouse model

• Published in: Molecular medicine reports Vol. 22; no. 1; pp. 362 - 370
• Main Authors: Tan, Qing-Long, Zhou, Chang-Yuan, Cheng, Lin, Luo, Min, Liu, Chun-Ping, Xu, Wen-Xing, Zhang, Xian, Zeng, Xing
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications UK Ltd 01.07.2020; D.A. Spandidos
• Subjects: Adjuvants, Immunologic - pharmacology; Adjuvants, Immunologic - therapeutic use; Animals; Antibodies; Antigens; Bacillus; Bacillus Calmette-Guerin vaccine; BCG; BCG Vaccine - immunology; BCG Vaccine - therapeutic use; Bladder cancer; Bone marrow; c-Fos protein; CD11b antigen; Cell activation; Cell Line, Tumor; Cytokines; Cytokines - analysis; Cytokines - immunology; Disease Models, Animal; Gene Deletion; Growth factors; Humans; Immune response; Immune system; Immunotherapy; Inflammation; Injection; Interleukin 12; Interleukin 6; Interleukin Receptor Common gamma Subunit - genetics; Intravenous administration; Laboratory animals; Ligands; Macrophage Activation; Macrophages; Macrophages - immunology; Male; Mice, Inbred NOD; Mice, SCID; Monocyte chemoattractant protein 1; Monocytes; Mycobacterium bovis - immunology; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - immunology; Urinary Bladder Neoplasms - therapy
• ISSN: 1791-2997; 1791-3004; 1791-3004
• DOI: 10.3892/mmr.2020.11090

Bacillus Calmette‑Guérin (BCG) is considered to be a successful biotherapy for treating bladder cancer (BCa). However, the underlying mechanisms of BCG have not been completely clarified, to date. The role of macrophages in BCG therapy for BCa has still not been determined in vivo. In the present study, the role and potential mechanism of BCG (0.25, 1.25 and 6.25 µg/mouse; intravenous) immunotherapy for BCa was investigated in a NOD/scid IL2Rg‑/‑ (NSI) mouse model by targeting macrophages in vivo. Notably, it was observed that NSI mice with T24 BCa cells displayed high levels of the macrophage marker CD11b+ F4/80+ after injection via the tail vein of live BCG, as well as a significant reduction in tumor volume. The levels of the inflammatory and macrophage maturation cytokines, such as tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6, IL‑12P70, TNF superfamily member 11 and monocyte chemotactic protein 1, were significantly increased in the serum and the tumor supernatant compared to that in normal control subjects. Furthermore, BCG promoted the expression of the pro‑differential genes Spi‑1 proto‑oncogene, early growth response protein 1, nuclear factor (NF)‑κB and proto‑oncogene c‑Fos in bone marrow. In conclusion, these observations indicate that the injection of live BCG can target macrophages against bladder tumor growth in vivo. The mechanism is likely related to the promotion of macrophage maturation, immune activation and increased numbers of macrophages infiltrating the bladder tumor.