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.
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Donnele
authors.initials: D
authors.lastname: Daley
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Vishnu R
authors.initials: VR
authors.lastname: Mani
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Navyatha
authors.initials: N
authors.lastname: Mohan
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Akkad
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Ochi
authors.affiliation: Department of Chemistry, New York University, New York, New York, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Heindel
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Ki Buom
authors.initials: KB
authors.lastname: Lee
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Constantinos P
authors.identifier: http://orcid.org/0000-0003-2740-3259
authors.initials: CP
authors.lastname: Zambirinis
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Gautam Sd Balasubramania
authors.initials: GSB
authors.lastname: Pandian
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Shivraj
authors.initials: S
authors.lastname: Savadkar
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Torres-Hernandez
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Nayak
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: Wang
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Mautin
authors.initials: M
authors.lastname: Hundeyin
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Diskin
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Berk
authors.initials: B
authors.lastname: Aykut
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Gregor
authors.initials: G
authors.lastname: Werba
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Rocky M
authors.identifier: http://orcid.org/0000-0002-8062-7246
authors.initials: RM
authors.lastname: Barilla
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Rodriguez
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Gardner
authors.affiliation: Department of Chemistry, New York University, New York, New York, USA.
authors.forename: Lara K
authors.initials: LK
authors.lastname: Mahal
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Ueberheide
authors.affiliation: S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.|Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
authors.forename: George
authors.initials: G
authors.lastname: Miller
mesh_terms: D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D037161:Galectins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D037181:Lectins, C-Type / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D010183:Pancreatic Ducts / Q000166:cytology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000072377:Syk Kinase / Q000235:genetics / Q000378:metabolism; D019139:Tumor Escape / Q000235:genetics* / Q000276:immunology; D000099181:Dectin-1
chemical_list: D037161:Galectins; D037181:Lectins, C-Type; D000072377:Syk Kinase; D000099181:Dectin-1; C105032:LGALS9 protein, human; C508186:galectin 9, mouse