Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis

• Published in: Cell Vol. 174; no. 1; pp. 88 - 101.e16
• Main 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.06.2018
• Subjects: adaptive immunity; Adaptive Immunity - drug effects; Animals; antigen processing; Azoxymethane - toxicity; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - metabolism; Cell Membrane Permeability; colon cancer; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; cross dressing; Cytokines - metabolism; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Female; Ferrous Compounds - metabolism; Humans; Interferon-gamma - metabolism; Interferon-gamma - pharmacology; intestinal epithelial cells; Intestinal Mucosa - cytology; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; lysosomal membrane permeabilization; Lysosomes - metabolism; Male; Mice; Mice, Knockout; mitophagy; Mitophagy - drug effects; Stat3; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Survival Rate; intestinal epithelial cells; mitophagy; colon cancer; cross dressing; lysosomal membrane permeabilization; Stat3; antigen processing; adaptive immunity
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.05.028

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. [Display omitted] •Increased mitophagy in IECs triggers lysosomal membrane permeabilization•Lysosomal membrane permeabilization enhances antigen presentation in IECs•Enhanced antigen presentation in IECs augments MHC class I presentation•Mitophagy and lysosomal integrity in IECs regulate anti-tumor immunity Enhanced mitophagy in intestinal epithelial cells promotes anti-tumor immunity through increasing lysosomal membrane permeabilization that augments MHC I presentation and CD8+ T cell activation.