Mitophagy in intestinal epithelial cells triggers adaptive immunity during tumorigenesis
- Author(s)
- Ziegler, PK; Bollrath, J; Pallangyo, CK; Matsutani, T; Canli, O; De Oliveira, T; Diamanti, MA; Muller, N; Gamrekelashvili, J; Putoczki, T; Horst, D; Mankan, AK; Oner, MG; Muller, S; Muller-Hocker, J; Kirchner, T; Slotta-Huspenina, J; Taketo, MM; Reinheckel, T; Drose, S; Larner, AC; Wels, WS; Ernst, M; Greten, TF; Arkan, MC; Korn, T; Wirth, D; Greten, FR;
- 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
- Research Division(s)
- Inflammation
- PubMed ID
- 29909986
- Publisher's Version
- https://doi.org/10.1016/j.cell.2018.05.028
- Terms of Use/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