Plasmacytoid dendritic cells regulate colitis-associated tumorigenesis by controlling myeloid-derived suppressor cell infiltration

• Published in: Cancer letters 2020-11, Vol.493, p.102-112
• Main Authors: Hong, Eun-Hye, Cho, Jaewon, Ahn, Jae-hee, Kwon, Bo-Eun, Kweon, Mi-Na, Seo, Sang-Uk, Yoon, Byung-Il, Chang, Sun-Young, Ko, Hyun-Jeong
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Azoxymethane; Azoxymethane - adverse effects; Body Weight; Bone marrow; Cell Line, Tumor; Colitis; Colitis - chemically induced; Colitis - complications; Colitis - genetics; Colon cancer; Colonic Neoplasms - chemically induced; Colonic Neoplasms - genetics; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Colorectal cancer; Colorectal carcinoma; Cytokines; Dendritic cells; Dendritic Cells - metabolism; Dextran; Dextran sulfate; Dextran Sulfate - adverse effects; Disease Models, Animal; Disease Progression; Drinking water; Female; Gene Knockout Techniques; Granulocytes; Inflammation; Inflammatory bowel disease; Interferon; Laboratories; Ligands; Membrane Glycoproteins - genetics; Metastases; Mice; Mucosa; Myeloid-derived suppressor cell; Myeloid-Derived Suppressor Cells - metabolism; Pathogens; Plasmacytoid dendritic cell; Signal Transduction; TLR3 protein; TLR7 protein; Toll-like receptor; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 7 - genetics; Toll-like receptors; Tumor necrosis factor-TNF; Tumorigenesis; Tumors; Viral infections
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.08.007

Toll-like receptor (TLR)3 and TLR7 are important for stimulating plasmacytoid dendritic cells (pDCs), which secrete type I interferon. Mice deficient for TLR3 and TLR7 (TLR3−/−TLR7−/−) reportedly exhibit deteriorated colitis because of impaired pDCs. However, the role of pDCs in tumorigenesis-associated inflammation progression has not been studied. We treated wild-type or TLR3−/−TLR7−/− mice with dextran sulfate sodium (DSS) and/or azoxymethane (AOM) and examined colon mucosa, measured body weight and colon length of mice, and examined pDC and myeloid-derived suppressor cell (MDSC) accumulation. Further, we depleted pDCs in AOM/DSS-treated wild-type mice by treating them with anti-PDCA-1 antibodies. We found that MDSCs significantly increased, while pDCs decreased in TLR3−/−TLR7−/− mice. Moreover, TLR3−/−TLR7−/− mice developed colitis-associated colon cancer following AOM/DSS treatment. Additionally, we showed that a defect in TLR7 of pDCs is responsible for the aggravation of colitis-associated colon cancer. Further, we showed that TLR7 ligand mitigates colitis-associated colon cancer. Collectively, our results demonstrate that gut pDCs play a crucial role in reducing colorectal cancer development via the regulation of infiltrating MDSCs. •We found that MDSC number significantly increased, while pDCs decreased in TLR3−/−TLR7−/− mice.•Additionally, defect in TLR7s of pDCs is responsible for the aggravation of colitis-associated colon cancer.•And we also show TLR7 ligand mitigate the colitis-associated colon cancer.