Blocking Dectin-1 prevents colorectal tumorigenesis by suppressing prostaglandin E2 production in myeloid-derived suppressor cells and enhancing IL-22 binding protein expression

Ce Tang (), Haiyang Sun, Motohiko Kadoki, Wei Han, Xiaoqi Ye, Yulia Makusheva, Jianping Deng, Bingbing Feng, Ding Qiu, Ying Tan, Xinying Wang, Zehao Guo, Chanyan Huang, Sui Peng, Minhu Chen, Yoshiyuki Adachi, Naohito Ohno, Sergio Trombetta and Yoichiro Iwakura ()
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Ce Tang: Sun Yat-sen University, No.58, Zhong Shan Er Lu
Haiyang Sun: Sun Yat-sen University
Motohiko Kadoki: Tokyo University of Science
Wei Han: Tokyo University of Science
Xiaoqi Ye: Sun Yat-sen University, No.58, Zhong Shan Er Lu
Yulia Makusheva: Tokyo University of Science
Jianping Deng: Sun Yat-sen University
Bingbing Feng: Sun Yat-sen University
Ding Qiu: Sun Yat-sen University
Ying Tan: Sun Yat-sen University
Xinying Wang: Sun Yat-sen University
Zehao Guo: Sun Yat-sen University, No.58, Zhong Shan Er Lu
Chanyan Huang: Sun Yat-sen University
Sui Peng: Sun Yat-sen University, No.58, Zhong Shan Er Lu
Minhu Chen: Sun Yat-sen University, No.58, Zhong Shan Er Lu
Yoshiyuki Adachi: Tokyo University of Pharmacy and Life Sciences, Hachioji
Naohito Ohno: Tokyo University of Pharmacy and Life Sciences, Hachioji
Sergio Trombetta: Boehringer Ingelheim USA
Yoichiro Iwakura: Tokyo University of Science

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Dectin-1 (gene Clec7a), a receptor for β-glucans, plays important roles in the host defense against fungi and immune homeostasis of the intestine. Although this molecule is also suggested to be involved in the regulation of tumorigenesis, the role in intestinal tumor development remains to be elucidated. In this study, we find that azoxymethane-dextran-sodium-sulfate-induced and ApcMin-induced intestinal tumorigenesis are suppressed in Clec7a−/− mice independently from commensal microbiota. Dectin-1 is preferentially expressed on myeloid-derived suppressor cells (MDSCs). In the Clec7a−/− mouse colon, the proportion of MDSCs and MDSC-derived prostaglandin E2 (PGE2) levels are reduced, while the expression of IL-22 binding protein (IL-22BP; gene Il22ra2) is upregulated. Dectin-1 signaling induces PGE2-synthesizing enzymes and PGE2 suppresses Il22ra2 expression in vitro and in vivo. Administration of short chain β-glucan laminarin, an antagonist of Dectin-1, suppresses the development of mouse colorectal tumors. Furthermore, in patients with colorectal cancer (CRC), the expression of CLEC7A is also observed in MDSCs and correlated with the death rate and tumor severity. Dectin-1 signaling upregulates PGE2-synthesizing enzyme expression and PGE2 suppresses IL22RA2 expression in human CRC-infiltrating cells. These observations indicate a role of the Dectin-1-PGE2-IL-22BP axis in regulating intestinal tumorigenesis, suggesting Dectin-1 as a potential target for CRC therapy.

Date: 2023
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DOI: 10.1038/s41467-023-37229-x

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