Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance
Donnele Daley,Vishnu R. Mani,Navyatha Mohan,Neha Akkad,Atsuo Ochi,Daniel W. Heindel,Ki Buom Lee,Constantinos P. Zambirinis,Gautam S.D. Balasubramania Pandian,Shivraj Savadkar,Alejandro Torres-Hernandez,Shruti Nayak,Ding Wang,Mautin Hundeyin,Brian Diskin,Berk Aykut,Gregor Werba,Rocky Barilla,Robert Rodriguez,Steven Chang,Lawrence B. Gardner,Lara K. Mahal,Beatrix Ueberheide,George Miller +23 more
TLDR
It is 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, and suggests that targeting dectIn 1 signaling is an attractive strategy for developing an immunotherapy for PDA.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.read more
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Understanding the tumor immune microenvironment (TIME) for effective therapy.
Mikhail Binnewies,Edward W. Roberts,Kelly Kersten,Vincent Chan,Douglas F. Fearon,Miriam Merad,Lisa M. Coussens,Dmitry I. Gabrilovich,Suzanne Ostrand-Rosenberg,Suzanne Ostrand-Rosenberg,Catherine C. Hedrick,Robert H. Vonderheide,Mikael J. Pittet,Rakesh K. Jain,Weiping Zou,T. Kevin Howcroft,Elisa C. Woodhouse,Robert A. Weinberg,Matthew F. Krummel +18 more
TL;DR: By parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient’s tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
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The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression
Smruti Pushalkar,Mautin Hundeyin,Donnele Daley,Constantinos P. Zambirinis,Emma Kurz,Ankita Mishra,Navyatha Mohan,Berk Aykut,Mykhaylo Usyk,Luisana E. Torres,Gregor Werba,Kevin Zhang,Yuqi Guo,Qianhao Li,Neha Akkad,Sarah Lall,Benjamin Wadowski,Johana Gutierrez,Juan A. Kochen Rossi,Jeremy Herzog,Brian Diskin,Alejandro Torres-Hernandez,Josh Leinwand,Wei Wang,Pardeep S. Taunk,Shivraj Savadkar,Malvin N. Janal,Anjana Saxena,Xin Li,Deirdre Jill Cohen,R. Balfour Sartor,R. Balfour Sartor,Deepak Saxena,George Miller,George Miller +34 more
TL;DR: It is found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy, and that the microbiome has potential as a therapeutic target in the modulation of disease progression.
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Diversity, Mechanisms, and Significance of Macrophage Plasticity
TL;DR: Macrophage plasticity, an essential component of chronic inflammation, and its involvement in diverse human diseases, most notably cancer, is discussed here as a paradigm.
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C-type lectins in immunity and homeostasis
TL;DR: Recently discovered roles for C-type lectins in development, homeostasis, cell death, cancer and autoimmune and inflammatory diseases extend the functions of this superfamily beyond their well-recognized involvement in antimicrobial responses.
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Trp53R172H and kmsg12d cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
Sunil R. Hingorani,Lifu Wang,Asha S. Multani,Chelsea Combs,Therese B. Deramaudt,Ralph H. Hruban,Anil K. Rustgi,Sandy Chang,David A. Tuveson +8 more
TL;DR: In this article, the authors defined the genetic requirements for pancreatic ductal adenocarcinoma (PDA) and targeted concomitant endogenous expression of Trp53 R172H and Kras G12D to reveal the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease.
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TL;DR: Targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas reveals the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease.
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