Journal article
Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis
PK Ziegler, J Bollrath, CK Pallangyo, T Matsutani, Ö Canli, T De Oliveira, MA Diamanti, N Müller, J Gamrekelashvili, T Putoczki, D Horst, AK Mankan, MG Öner, S Müller, J Müller-Höcker, T Kirchner, J Slotta-Huspenina, MM Taketo, T Reinheckel, S Dröse Show all
Cell | CELL PRESS | Published : 2018
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. ..
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Awarded by National Cancer Institute
Funding Acknowledgements
We thank Kerstin Burmeister, Saskia Ettl, Kathleen Mohs, Hana Kunkel, Christin Danneil, Natalia Delis, and Eva Rudolf for technical assistance, as well as the Histology and Flow Cytometry Core Facilities at the Georg-Speyer-Haus. We are grateful to Johanna Joyce and Masaaki Komatsu for generously providing Ctss<SUP>-/-</SUP> and floxed Atg7 mice, respectively, and we thank Chris Chang for generously providing IP-1. The plasmid pTRE-Tight-MitoTimer was a kind gift from Roberta Gottlieb (Addgene plasmid # 50547), DEC205-OVA was a kind gift from Anne Krug, and pES.1-2(M2N)p was kindly provided by Rainer Loew. We gratefully acknowledge the TUM-MRI-Tissue Biobank at the Department of Pathology, Klinikum rechts der Isar, and the Victorian Cancer Biobank for providing colon cancer specimens. We would like to thank Lisa Sevenich, Firouzeh Korangy, Ari Waisman, and Thomas Blankenstein for helpful discussions. This work was supported in part by the LOEWE Center for Cell and Gene Therapy Frankfurt (CGT, III L 4-518/17.004) and institutional funds from the Georg-Speyer-Haus, as well as grants from the Deutsche Forschungsgemeinschaft (DFG) (SFB 850 Project B7 to T.R.; Gr1916/5-1, FOR2438 Gr1916/11-1, SFB 815, 1177, and 1292 to F.R.G.).