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

D Daley, VR Mani, N Mohan, N Akkad, A Ochi… - Nature medicine, 2017 - nature.com
D Daley, VR Mani, N Mohan, N Akkad, A Ochi, DW Heindel, KB Lee, CP Zambirinis
Nature medicine, 2017nature.com
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 …
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.
nature.com