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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Daley, D; Mani, VR; Mohan, N; Akkad, N; Ochi, A; Heindel, DW; Lee, KB; Zambirinis, CP; Pandian, GSB; Savadkar, S; Torres-Hernandez, A; Nayak, S; Wang, D; Hundeyin, M; Diskin, B; Aykut, B; Werba, G; Barilla, RM; Rodriguez, R; Chang, S; Gardner, L; Mahal, LK; Ueberheide, B; Miller, G

Published Date

  • May 2017

Published In

Volume / Issue

  • 23 / 5

Start / End Page

  • 556 - 567

PubMed ID

  • 28394331

Pubmed Central ID

  • 28394331

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

International Standard Serial Number (ISSN)

  • 1078-8956

Digital Object Identifier (DOI)

  • 10.1038/nm.4314

Language

  • eng