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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.
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
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