TY - JOUR
T1 - Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance
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
N1 - Publisher Copyright:
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
PY - 2017/5/1
Y1 - 2017/5/1
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.
AB - 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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U2 - 10.1038/nm.4314
DO - 10.1038/nm.4314
M3 - Article
C2 - 28394331
AN - SCOPUS:85017279150
SN - 1078-8956
VL - 23
SP - 556
EP - 567
JO - Nature Medicine
JF - Nature Medicine
IS - 5
ER -