Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance
| Autor: | Ding Wang, Ki Buom Lee, Gautam S.D. Balasubramania Pandian, Neha Akkad, Donnele Daley, Constantinos P. Zambirinis, Berk Aykut, Beatrix Ueberheide, George Miller, Brian Diskin, Shruti Nayak, Alejandro Torres-Hernandez, Lara K. Mahal, Steven Chang, Vishnu R. Mani, Gregor Werba, Robert Rodriguez, Lawrence B. Gardner, Atsuo Ochi, Shivraj Savadkar, Navyatha Mohan, Rocky Barilla, Mautin Hundeyin, Daniel W. Heindel |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Carcinogenesis Galectins medicine.medical_treatment Blotting Western education T cells Inflammation Biology Mass Spectrometry Article General Biochemistry Genetics and Molecular Biology Immune tolerance Mice 03 medical and health sciences Immune system Immunity Immune Tolerance medicine Animals Humans Immunoprecipitation Syk Kinase Macrophage Lectins C-Type Galectin Mice Knockout Innate immune system Pancreatic Ducts Epithelial Cells Pancreatic cancer General Medicine Immunotherapy Flow Cytometry Immunohistochemistry 3. Good health Pancreatic Neoplasms 030104 developmental biology Myeloid-derived suppressor cells Gene Knockdown Techniques Immunology Kras Cancer research Tumor Escape medicine.symptom Carcinoma Pancreatic Ductal |
| Zdroj: | Nature medicine |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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