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

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


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.

MeSH terms

  • Animals
  • Blotting, Western
  • Carcinogenesis / genetics
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / metabolism
  • Epithelial Cells / metabolism
  • Flow Cytometry
  • Galectins / metabolism*
  • Gene Knockdown Techniques
  • Humans
  • Immune Tolerance / genetics
  • Immunohistochemistry
  • Immunoprecipitation
  • Lectins, C-Type / genetics*
  • Lectins, C-Type / immunology
  • Lectins, C-Type / metabolism
  • Mass Spectrometry
  • Mice
  • Mice, Knockout
  • Pancreatic Ducts / cytology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / metabolism
  • Syk Kinase / genetics
  • Syk Kinase / metabolism
  • Tumor Escape / genetics*
  • Tumor Escape / immunology


  • Galectins
  • LGALS9 protein, human
  • Lectins, C-Type
  • dectin 1
  • galectin 9, mouse
  • Syk Kinase