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ItemOpen Access
Macrophages in Nonalcoholic Steatohepatitis: Friend or Foe?
(EMJ Hepatology) Grunhut, Joel; Wang, Wei; Aykut, Berk; Gakhal, Inderdeep; Torres-Hernandez, Alejandro; Miller, George
Nonalcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease that is characterised by steatosis, chronic inflammation, and hepatocellular injury with or without fibrosis. The role and activation of macrophages in the pathogenesis of NASH is complex and is being studied for possible therapeutic options to help the millions of people diagnosed with the disease. The purpose of this review is to discuss the pathogenesis of NASH through the activation and role of Kupffer cells and other macrophages in causing inflammation and progression of NASH. Furthermore, this review aims to outline some of the current therapeutic options targeting the pathogenesis of NASH.
ItemOpen 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, George
Abstract 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
ItemOpen Access
EMX2 gene expression predicts liver metastasis and survival in colorectal cancer
(BMC Cancer, 2017-12) Aykut, Berk; Ochs, Markus; Radhakrishnan, Praveen; Brill, Adrian; Höcker, Hermine; Schwarz, Sandra; Weissinger, Daniel; Kehm, Roland; Kulu, Yakup; Ulrich, Alexis; Schneider, Martin
ItemOpen Access
Specialized dendritic cells induce tumor-promoting IL-10+IL-17+ FoxP3neg regulatory CD4+ T cells in pancreatic carcinoma
(Nature Communications) Barilla, Rocky M; Diskin, Brian; Caso, Raul Caso; Lee, Ki Buom; Mohan, Navyatha; Buttar, Chandan; Adam, Salma; Sekendiz, Zennur; Wang, Junjie; Salas, Ruben D; Cassini, Marcelo F; Karlen, Jason; Sundberg, Belen; Akbar, Hashem; Levchenko, Dmitry; Gakhal, Inderdeep; Gutierrez, Johana; Wang, Wei; Hundeyin, Mautin; Torres-Hernandez, Alejandro; Leinwand, Joshua; Kurz, Emma; Rossi, Juan A Kochen; Mishra, Ankita; Liria, Miguel; Sanchez, Gustavo; Panta, Jyoti; Loke, P’ng; Aykut, Berk; Miller, George
AbstractThe drivers and the specification of CD4+ T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique TH-program. Specifically, CD11b+CD103− DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3neg tumor-promoting IL-10+IL-17+IFNγ+ regulatory CD4+ T cells. The balance between this distinctive TH program and canonical FoxP3+ TREGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This TH-signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b+CD103− DC promote CD4+ T cell tolerance in PDA which may underscore its resistance to immunotherapy.
ItemOpen Access
CD95 promotes metastatic spread via Sck in pancreatic ductal adenocarcinoma
(Cell Death & Differentiation, 2015-07) Teodorczyk, M; Kleber, S; Wollny, D; Sefrin, JP; Aykut, B; Mateos, A; Herhaus, P; Sancho-Martinez, I; Hill, O; Gieffers, C; Sykora, J; Weichert, W; Eisen, C; Trumpp, A; Sprick, MR; Bergmann, F; Welsch, T; Martin-Villalba, A