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.
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Change history
29 November 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41591-021-01428-0
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Acknowledgements
This work was supported by grants from the National Pancreas Foundation (to C.P.Z.), the AACR-Pancreatic Cancer Action Network (to G.M.), the Lustgarten Foundation (to G.M.), Department of Defense Peer Reviewed Medical Research Program (to G.M.), Panpaphian Association of America (to C.Z.), the Irene and Bernard Schwartz Fellowship in GI Oncology (D.D.), and National Institute of Health Awards CA155649 (to G.M.), CA168611 (to G.M.), CA193111 (to G.M. and A.T.-H.) and the NYU School of Medicine Office of Therapeutics Alliances. We thank the New York University Langone Medical Center (NYU LMC) Histopathology Core Facility, the NYU LMC Flow Cytometry Core Facility, the NYU LMC Microscopy Core Facility and the NYU LMC BioRepository Center, each supported in part by the Cancer Center Support grant P30CA016087 and by grant UL1 TR000038 from the National Center for the Advancement of Translational Science (NCATS). Clec7a−/− mice were a gift of G. Brown (University of Aberdeen, UK). KC mice were a gift of D. Bar-Sagi and KPC mice were a gift of M. Philips, both New York University). The pCI-neo-cOVA vector was a gift of M. Castro (University of Michigan).
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D.D. and V.R.M. (project leadership, data collection and analysis, manuscript preparation); N.M. (flow cytometry, western blotting, in vivo experiments and manuscript preparation); N.A. (IHC, IF, flow cytometry and in vivo experiments); A.O. (immunoprecipitation, binding assays, ELISA and western blotting); K.B.L., G.S.D.B.P., S.S. and R.R. (flow cytometry and in vivo experiments); D.W.H. (immunoprecipitation and biochemical analysis); S.N. (mass spectroscopy); D.W. (cell line transfection); G.W. (in vivo experiments); C.P.Z. (data collection and mouse breeding); R.M.B., A.T.-H., M.H., B.D. and B.A. (technical assistance in diverse in vivo and in vitro experiments), S.C. (data analysis), L.G. (cell-line transfection), L.K.M. (immunoprecipitation and biochemical analysis); B.U. (mass spectroscopy); G.M. (project design and leadership, data analysis and manuscript preparation).
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G.M. is a cofounder and Scientific Advisory Board Member of Nybo Therapeutics.
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Daley, D., Mani, V., Mohan, N. et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat Med 23, 556–567 (2017). https://doi.org/10.1038/nm.4314
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DOI: https://doi.org/10.1038/nm.4314
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