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.
Author Info: (1) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (2) S.A. Localio Laboratory, Department of Surgery, New York Un
Author Info: (1) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (2) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (3) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (4) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (5) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (6) Department of Chemistry, New York University, New York, New York, USA. (7) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (8) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (9) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (10) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (11) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (12) Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA. (13) Department of Medicine, New York University School of Medicine, New York, New York, USA. (14) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (15) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (16) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (17) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (18) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (19) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (20) S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA. (21) Department of Medicine, New York University School of Medicine, New York, New York, USA. (22) Department of Chemistry, New York University, New York, New York, USA. (23) Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA. (24) 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.
