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 Chang; Lawrence Gardner; Lara K. Mahal; Beatrix Ueberheide; George Miller

doi:10.1038/nm.4314

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

Chemistry

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	556-567
Number of pages	12
Journal	Nature Medicine
Volume	23
Issue number	5
DOIs	https://doi.org/10.1038/nm.4314
State	Published - May 1 2017

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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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

Daley, D, Mani, VR, Mohan, N, Akkad, N, Ochi, A, Heindel, DW, Lee, KB, Zambirinis, CP, Pandian, GSDB, 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 2017, 'Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance', Nature Medicine, vol. 23, no. 5, pp. 556-567. https://doi.org/10.1038/nm.4314

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title = "Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance",

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.",

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AU - Daley, Donnele

AU - Mani, Vishnu R.

AU - Mohan, Navyatha

AU - Akkad, Neha

AU - Ochi, Atsuo

AU - Heindel, Daniel W.

AU - Lee, Ki Buom

AU - Zambirinis, Constantinos P.

AU - Pandian, Gautam S.D.Balasubramania

AU - Savadkar, Shivraj

AU - Torres-Hernandez, Alejandro

AU - Nayak, Shruti

AU - Wang, Ding

AU - Hundeyin, Mautin

AU - Diskin, Brian

AU - Aykut, Berk

AU - Werba, Gregor

AU - Barilla, Rocky M.

AU - Rodriguez, Robert

AU - Chang, Steven

AU - Gardner, Lawrence

AU - Mahal, Lara K.

AU - Ueberheide, Beatrix

AU - Miller, George

PY - 2017/5/1

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N2 - 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.

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

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