Cell
Volume 174, Issue 1, 28 June 2018, Pages 88-101.e16
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Article
Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis

https://doi.org/10.1016/j.cell.2018.05.028Get rights and content
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Highlights

  • 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

Summary

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

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

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