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

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 Apc^Min-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.

The effect of β-glucans and their receptor Dectin-1 in tumor development remains controversial. Here the authors show that Dectin-1 signaling promotes the development of colorectal cancer (CRC) by inducing prostaglandin E2 production in myeloid-derived suppressor cells and by suppressing IL-22BP expression, suggesting dectin-1 blockade as a potential therapeutic target for CRC.