Mitophagy in intestinal epithelial cells triggers adaptive immunity during tumorigenesis

• Paul K. Ziegler ^[1] ; Julia Bollrath ^[2] ; Charles K. Pallangyo ^[1]
  1. [1] Institute for Tumor Biology and Experimental Therapy
  2. [2] Institute for Tumor Biology and Experimental Therapy, Georg
• Localización: Cell, ISSN 0092-8674, Vol. 174, Nº. 1, 2018, págs. 88-101
• Idioma: inglés
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• Resumen

  • 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.