Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis Academic Article uri icon

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. 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.

authors

  • Ziegler, Paul K
  • Bollrath, Julia
  • Pallangyo, Charles K
  • Matsutani, Takaji
  • Canli, Özge
  • De Oliveira, Tiago
  • Diamanti, Michaela A
  • Müller, Nina
  • Gamrekelashvili, Jaba
  • Putoczki, Tracy
  • Horst, David
  • Mankan, Arun K
  • Öner, Meryem G
  • Müller, Susanna
  • Müller-Höcker, Josef
  • Kirchner, Thomas
  • Slotta-Huspenina, Julia
  • Taketo, M Mark
  • Reinheckel, Thomas
  • Dröse, Stefan
  • Larner, Andrew C
  • Wels, Winfried S
  • Ernst, Matthias
  • Greten, Tim F
  • Arkan, Melek C
  • Korn, Thomas
  • Wirth, Dagmar
  • Greten, Florian R

publication date

  • 2018

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