Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis
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 intes...
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Published in | Cell Vol. 174; no. 1; pp. 88 - 101.e16 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
28.06.2018
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
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•Increased mitophagy in IECs triggers lysosomal membrane permeabilization•Lysosomal membrane permeabilization enhances antigen presentation in IECs•Enhanced antigen presentation in IECs augments MHC class I presentation•Mitophagy and lysosomal integrity in IECs regulate anti-tumor immunity
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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS Conceptualization, P.K.Z., J.B., W.S.W., M.C.A., T.K., and F.R.G.; Methodology, P.K.Z., J.B., and F.R.G.; Investigation, P.K.Z., J.B., C.K.P., T.M., Ö.C., T.D., M.A.D., N.M., J.G., D.H., A.K.M., M.G.Ö., S.M., J.M.-H., and S.D.; Resources, T.P., J.S.-H., M.M.T., T.R., A.C.L., M.E., T.F.G., and D.W.; Writing-Original Draft, P.K.Z. and F.R.G.; Writing Review & Editing, P.K.Z. and F.R.G.; Visualization P.K.Z. and F.R.G.; Supervision T.K., W.S.W., and F.R.G.; and Funding Acquisition, F.R.G. |
ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2018.05.028 |