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Cell. 2018 Jun 28;174(1):88-101.e16. doi: 10.1016/j.cell.2018.05.028. Epub 2018 Jun 14.

Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis.

Author information

1
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am, Germany; Institute of Pathology, Frankfurt University Hospital, 60590 Frankfurt, Germany.
2
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am, Germany.
3
R&D Department, Repertoire Genesis Incorporation, Ibaraki, Osaka 567-0085, Japan.
4
Department of Nephrology, Medical School Hannover, 30625 Hannover, Germany.
5
Walter and Eliza Hall Institute of Medical Research, Melbourne VIC, Australia.
6
Institute of Pathology, Charité- Universitätsmedizin Berlin, 10117 Berlin, Germany.
7
Institute of Pathology, Ludwig-Maximilians-University, 80337 Munich, Germany.
8
Institute of Pathology, Ludwig-Maximilians-University, 80337 Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
9
Institute of Pathology of the Technical University Munich, 81675 Munich, Germany.
10
Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
11
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
12
Department of Anesthesiology, Frankfurt University Hospital, 60590 Frankfurt am, Germany.
13
Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
14
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
15
Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg VIC 3084, Australia.
16
National Institutes of Health, National Cancer Institute, Medical Oncology Branch, Bethesda, MD 20892, USA.
17
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Institute of Biochemistry II, Goethe University School of Medicine, 60590 Frankfurt am, Germany.
18
Department of Neurology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany.
19
Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany; Experimental Hematology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
20
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: greten@gsh.uni-frankfurt.de.

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.

KEYWORDS:

Stat3; adaptive immunity; antigen processing; colon cancer; cross dressing; intestinal epithelial cells; lysosomal membrane permeabilization; mitophagy

PMID:
29909986
PMCID:
PMC6354256
[Available on 2019-06-28]
DOI:
10.1016/j.cell.2018.05.028
[Indexed for MEDLINE]

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