期刊
NATURE MEDICINE
卷 23, 期 5, 页码 556-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4314
关键词
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资金
- National Pancreas Foundation
- AACR-Pancreatic Cancer Action Network
- Lustgarten Foundation
- Department of Defense
- Panpaphian Association of America
- Irene and Bernard Schwartz Fellowship in GI Oncology
- National Institute of Health [CA155649, CA168611, CA193111]
- NYU School of Medicine Office of Therapeutics Alliances
- National Center for the Advancement of Translational Science (NCATS) [UL1 TR000038]
- [P30CA016087]
The progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of intratumoral immune tolerance are uncertain. Dectin 1 is an innate immune receptor crucial for anti-fungal immunity, but its role in sterile inflammation and oncogenesis has not been well defined. Furthermore, non-pathogen-derived ligands for dectin 1 have not been characterized. We found that dectin 1 is highly expressed on macrophages in pancreatic ductal adenocarcinoma (PDA). Dectin 1 ligation accelerated the progression of PDA in mice, whereas deletion of Clec7a-the gene encoding dectin 1-or blockade of dectin 1 downstream signaling was protective. We found that dectin 1 can ligate the lectin galectin 9 in mouse and human PDA, which results in tolerogenic macrophage programming and adaptive immune suppression. Upon disruption of the dectin 1-galectin 9 axis, CD4(+) and CD8(+) T cells, which are dispensable for PDA progression in hosts with an intact signaling axis, become reprogrammed into indispensable mediators of anti-tumor immunity. These data suggest that targeting dectin 1 signaling is an attractive strategy for developing an immunotherapy for PDA.
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