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

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.

Citation

Donnele Daley, Vishnu R Mani, Navyatha Mohan, Neha Akkad, Atsuo Ochi, Daniel W Heindel, Ki Buom Lee, Constantinos P Zambirinis, Gautam Sd Balasubramania Pandian, Shivraj Savadkar, Alejandro Torres-Hernandez, Shruti Nayak, Ding Wang, Mautin Hundeyin, Brian Diskin, Berk Aykut, Gregor Werba, Rocky M Barilla, Robert Rodriguez, Steven Chang, Lawrence Gardner, Lara K Mahal, Beatrix Ueberheide, George Miller. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nature medicine. 2017 May;23(5):556-567

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PMID: 28394331

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