Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis

Abstract

<p id="P3">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. </p><p id="P4">Enhanced mitophagy in intestinal epithelial cells promotes anti-tumor immunity through increasing lysosomal membrane permeabilization that augments MHC I presentation and CD8+ T cell activation. </p><p id="P5"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/43bb9f3e-0437-4812-a8bc-21ac85c1bfaf/PubMedCentral/image/nihms-1001095-f0001.jpg"/> </div> </p>