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Nat Med. 2017 May;23(5):556-567. doi: 10.1038/nm.4314. Epub 2017 Apr 10.

Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance.

Author information

1
S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
2
Department of Chemistry, New York University, New York, New York, USA.
3
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
4
Department of Medicine, New York University School of Medicine, New York, New York, USA.
5
Department of Cell Biology, New York University School of Medicine, New York, New York, USA.

Abstract

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.

PMID:
28394331
PMCID:
PMC5419876
DOI:
10.1038/nm.4314
[Indexed for MEDLINE]
Free PMC Article

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