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

Eun-Hye Hong; Jaewon Cho; Jae-Hee Ahn; Bo-Eun Kwon; Mi-Na Kweon; Sang-Uk Seo; Byung-Il Yoon; Sun-Young Chang; Hyun-Jeong Ko

doi:10.1016/j.canlet.2020.08.007

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

Cancer Lett. 2020 Nov 28:493:102-112. doi: 10.1016/j.canlet.2020.08.007. Epub 2020 Aug 15.

Authors

Eun-Hye Hong¹, Jaewon Cho¹, Jae-Hee Ahn¹, Bo-Eun Kwon¹, Mi-Na Kweon², Sang-Uk Seo³, Byung-Il Yoon⁴, Sun-Young Chang⁵, Hyun-Jeong Ko⁶

Affiliations

¹ Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, 24341, South Korea.
² Mucosal Immunology Laboratory, Department of Convergence Medicine, University of Ulsan College of Medicine/Asan Medical Center, Seoul, 05505, South Korea.
³ Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, 05505, South Korea.
⁴ Laboratory of Histology and Molecular Pathogenesis, College of Veterinary Medicine, Kangwon National University, Chuncheon, 24341, South Korea.
⁵ Laboratory of Microbiology, College of Pharmacy, Ajou University, Suwon, 16499, South Korea.
⁶ Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, 24341, South Korea. Electronic address: hjko@kangwon.ac.kr.

PMID: 32810576
DOI: 10.1016/j.canlet.2020.08.007

Abstract

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.

Keywords: Colorectal cancer; Myeloid-derived suppressor cell; Plasmacytoid dendritic cell; Toll-like receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Azoxymethane / adverse effects
Body Weight
Cell Line, Tumor
Colitis / chemically induced
Colitis / complications*
Colitis / genetics
Colonic Neoplasms / chemically induced
Colonic Neoplasms / genetics
Colonic Neoplasms / immunology
Colonic Neoplasms / pathology*
Dendritic Cells / metabolism*
Dextran Sulfate / adverse effects
Disease Models, Animal
Disease Progression
Female
Gene Knockout Techniques
Membrane Glycoproteins / genetics*
Mice
Myeloid-Derived Suppressor Cells / metabolism*
Signal Transduction
Toll-Like Receptor 3 / genetics*
Toll-Like Receptor 7 / genetics*

Substances

Membrane Glycoproteins
TLR3 protein, mouse
Tlr7 protein, mouse
Toll-Like Receptor 3
Toll-Like Receptor 7
Dextran Sulfate
Azoxymethane