Mitophagy in intestinal epithelial cells triggers adaptive immunity during tumorigenesis
Journal Title
Cell
Publication Type
Journal Article in press
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.
Publisher
Cell Press
WEHI Research Division(s)
Inflammation
PubMed ID
29909986
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2018-06-27 09:13:30
Last Modified: 2018-06-27 09:37:07
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