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Ziegler, Paul K.; Bollrath, Julia; Pallangyo, Charles K.; Matsutani, Takaji; Canli, Oezge; De Oliveira, Tiago; Diamanti, Michaela A.; Müller, Nina; Gamrekelashvili, Jaba; Putoczki, Tracy; Horst, David; Mankan, Arun K.; Oener, Meryem G.; Müller, Susanna; Müller-Hoecker, Josef; Kirchner, Thomas; Slotta-Huspenina, Julia; Taketo, M. Mark; Reinheckel, Thomas; Droese, Stefan; Larner, Andrew C.; Wels, Winfried S.; Ernst, Matthias; Greten, Tim F.; Arkan, Melek C.; Korn, Thomas; Wirth, Dagmar; Greten, Florian R. (2018): Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis. In: Cell, Vol. 174, No. 1: pp. 88-101
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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/beta-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.