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

Donnele Daley, Vishnu R. Mani, Navyatha Mohan, Neha Akkad, Atsuo Ochi, Daniel W. Heindel, Ki Buom Lee, Constantinos P. Zambirinis, Gautam S.D.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 ChangLawrence Gardner, Lara K. Mahal, Beatrix Ueberheide, George Miller

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)556-567
Number of pages12
JournalNature Medicine
Volume23
Issue number5
DOIs
StatePublished - May 1 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Daley, D., Mani, V. R., Mohan, N., Akkad, N., Ochi, A., Heindel, D. W., Lee, K. B., Zambirinis, C. P., Pandian, G. S. D. B., Savadkar, S., Torres-Hernandez, A., Nayak, S., Wang, D., Hundeyin, M., Diskin, B., Aykut, B., Werba, G., Barilla, R. M., Rodriguez, R., ... Miller, G. (2017). Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nature Medicine, 23(5), 556-567. https://doi.org/10.1038/nm.4314