MZB1-mediated IgA secretion suppresses the development and progression of colorectal cancer triggered by gut inflammation

Yue Tang; Xiaoqian Feng; Qing Lu; Chaoqun Cui; Meiping Yu; Zichao Wen; Yingying Luan; Lulu Dong; Ziying Hu; Runyun Zhang; Chunhui Lu; Jie Liu; Reiko Shinkura; Koji Hase; Ji-Yang Wang

doi:10.1016/j.mucimm.2023.12.002

MZB1-mediated IgA secretion suppresses the development and progression of colorectal cancer triggered by gut inflammation

Mucosal Immunol. 2023 Dec 13:S1933-0219(23)00098-3. doi: 10.1016/j.mucimm.2023.12.002. Online ahead of print.

Authors

Yue Tang¹, Xiaoqian Feng¹, Qing Lu¹, Chaoqun Cui¹, Meiping Yu², Zichao Wen¹, Yingying Luan¹, Lulu Dong¹, Ziying Hu³, Runyun Zhang¹, Chunhui Lu¹, Jie Liu⁴, Reiko Shinkura⁵, Koji Hase⁶, Ji-Yang Wang⁷

Affiliations

¹ Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
² Department of Clinical Immunology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
³ Department of Microbiology and Immunology, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
⁴ Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China.
⁵ Laboratory of Immunology and Infection Control, Institute of Quantitative Biosciences, the University of Tokyo, Tokyo, Japan.
⁶ Division of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan.
⁷ Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China; Department of Clinical Immunology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China; Department of Microbiology and Immunology, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai 200052, China. Electronic address: wang@fudan.edu.cn.

PMID: 38101774
DOI: 10.1016/j.mucimm.2023.12.002

Abstract

Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of immunoglobulin (Ig)A in maintaining gut homeostasis and preventing inflammation has been well established. Our earlier work demonstrated that the marginal zone and B1 cell-specific protein (MZB1) promotes gut IgA secretion and its absence results in pronounced dextran sulfate sodium salt (DSS)-induced colitis. In the present study, we explored the role of MZB1 in CRC development using the azoxymethane (AOM)/DSS-induced CRC model. We observed an increase in both the number and size of the tumor nodules in Mzb1^-/- mice compared with Mzb1^+/+ mice. The increase in CRC development and progression in Mzb1^-/- mice was associated with reduced intestinal IgA levels, altered gut flora, and more severe gut and systemic inflammation. Oral administration of the monoclonal IgA, W27, alleviated both the gut inflammation and AOM/DSS-induced CRC. Notably, cohousing Mzb1^+/+ and Mzb1^-/- mice from the 10th day after birth led to similar CRC development. Our findings underscore the pivotal role of MZB1-mediated IgA secretion in suppressing the onset and progression of CRC triggered by gut inflammation. Moreover, our study highlights the profound impact of microbiota composition, modulated by gut IgA levels, on gut inflammation. Nonetheless, establishing a direct correlation between the severity of colitis and subsequent CRC development and the presence or absence of a particular microbiota is challenging.