Daley, DonneleMani, Vishnu RMohan, NavyathaAkkad, NehaOchi, AtsuoHeindel, Daniel WLee, Ki BuomZambirinis, Constantinos PPandian, Gautam Sd BalasubramaniaSavadkar, ShivrajTorres-Hernandez, AlejandroNayak, ShrutiWang, DingHundeyin, MautinDiskin, BrianAykut, BerkWerba, GregorBarilla, Rocky MRodriguez, RobertChang, StevenGardner, LawrenceMahal, Lara KUeberheide, BeatrixMiller, George2024-02-232024-02-232017-051078-89561546-170Xhttps://hdl.handle.net/10161/30179The 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.Pancreatic DuctsEpithelial CellsAnimalsMice, KnockoutHumansMiceCarcinoma, Pancreatic DuctalPancreatic NeoplasmsLectins, C-TypeGalectinsBlotting, WesternFlow CytometryImmunohistochemistryImmunoprecipitationImmune ToleranceTumor EscapeMass SpectrometryGene Knockdown TechniquesCarcinogenesisSyk KinaseJournal article