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Title: | Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis. | Austin Authors: | Ziegler, Paul K;Bollrath, Julia;Pallangyo, Charles K;Matsutani, Takaji;Canli, Özge;De Oliveira, Tiago;Diamanti, Michaela A;Müller, Nina;Gamrekelashvili, Jaba;Putoczki, Tracy;Horst, David;Mankan, Arun K;Öner, Meryem G;Müller, Susanna;Müller-Höcker, Josef;Kirchner, Thomas;Slotta-Huspenina, Julia;Taketo, M Mark;Reinheckel, Thomas;Dröse, Stefan;Larner, Andrew C;Wels, Winfried S;Ernst, Matthias ;Greten, Tim F;Arkan, Melek C;Korn, Thomas;Wirth, Dagmar;Greten, Florian R | Affiliation: | Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am, Germany Institute of Pathology, Frankfurt University Hospital, Frankfurt, Germany R&D Department, Repertoire Genesis Incorporation, Ibaraki, Osaka, Japan Department of Nephrology, Medical School Hannover, Hannover, Germany Walter and Eliza Hall Institute of Medical Research, Melbourne VIC, Australia Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany Institute of Pathology of the Technical University Munich, Munich, Germany Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert-Ludwigs-University Freiburg, Freiburg, Germany Department of Anesthesiology, Frankfurt University Hospital, Frankfurt am, Germany Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia National Institutes of Health, National Cancer Institute, Medical Oncology Branch, Bethesda, MD, USA Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt am, Germany Department of Neurology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstr. Braunschweig, Germany Experimental Hematology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, Germany School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia |
Issue Date: | 2018 | Date: | 2018-06-11 | Publication information: | Cell 2018; 174(1): 88-101.e16 | Abstract: | In colorectal cancer patients, a high density of cytotoxic CD8+ T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/β-catenin-dependent autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8+ T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization. Subsequent release of proteases into the cytoplasm augments MHC class I presentation and activation of CD8+ T cells via cross-dressing of dendritic cells. Thus, our findings highlight a so-far-unrecognized link between mitochondrial function, lysosomal integrity, and MHC class I presentation in IECs and suggest that therapies triggering mitophagy or inducing LMP in IECs may prove successful in shifting the balance toward anti-tumor immunity in colorectal cancer. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/17955 | DOI: | 10.1016/j.cell.2018.05.028 | ORCID: | 0000-0002-6399-1177 | Journal: | Cell | PubMed URL: | 29909986 | Type: | Journal Article | Subjects: | Stat3 adaptive immunity antigen processing colon cancer cross dressing intestinal epithelial cells lysosomal membrane permeabilization mitophagy |
Appears in Collections: | Journal articles |
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