Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis

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

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

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.

Original languageEnglish
Pages (from-to)88-101.e16
JournalCell
Volume174
Issue number1
DOIs
StatePublished - 28 Jun 2018
Externally publishedYes

Keywords

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

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