Browsing by Author "Zambirinis, Constantinos P"
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Item Open Access Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance.(Nature medicine, 2017-05) Daley, Donnele; Mani, Vishnu R; Mohan, Navyatha; Akkad, Neha; Ochi, Atsuo; Heindel, Daniel W; Lee, Ki Buom; Zambirinis, Constantinos P; Pandian, Gautam Sd Balasubramania; Savadkar, Shivraj; Torres-Hernandez, Alejandro; Nayak, Shruti; Wang, Ding; Hundeyin, Mautin; Diskin, Brian; Aykut, Berk; Werba, Gregor; Barilla, Rocky M; Rodriguez, Robert; Chang, Steven; Gardner, Lawrence; Mahal, Lara K; Ueberheide, Beatrix; Miller, GeorgeThe 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.Item Open Access The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression(Cancer Discovery, 2018-04-01) Pushalkar, Smruti; Hundeyin, Mautin; Daley, Donnele; Zambirinis, Constantinos P; Kurz, Emma; Mishra, Ankita; Mohan, Navyatha; Aykut, Berk; Usyk, Mykhaylo; Torres, Luisana E; Werba, Gregor; Zhang, Kevin; Guo, Yuqi; Li, Qianhao; Akkad, Neha; Lall, Sarah; Wadowski, Benjamin; Gutierrez, Johana; Kochen Rossi, Juan Andres; Herzog, Jeremy W; Diskin, Brian; Torres-Hernandez, Alejandro; Leinwand, Josh; Wang, Wei; Taunk, Pardeep S; Savadkar, Shivraj; Janal, Malvin; Saxena, Anjana; Li, Xin; Cohen, Deirdre; Sartor, R Balfour; Saxena, Deepak; Miller, GeorgeAbstract We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression. Significance: We 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. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. Cancer Discov; 8(4); 403–16. ©2018 AACR. See related commentary by Riquelme et al., p. 386. This article is highlighted in the In This Issue feature, p. 371