Exploring epithelial cell mitophagy as an inducer of adaptive immunity (E05*)

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In a model of intestinal tumorigenesis, we recently found that absence of STAT3 resulted in elevated mitophagy in intestinal epithelial cells (IEC), which in turn led to lysosomal membrane permeabilization (LMP), thereby enhancing antigen presentation and activation of CD8+ T cells. In this proposal, we plan to define the molecular mechanisms that trigger mitophagy and to screen for inducers of mitophagy that subsequently initiate LMP. Furthermore, we will evaluate whether mitophagy and LMP induction is capable of sensitizing established tumors to checkpoint inhibition and will examine whether mitophagy and LMP induction represents a common mechanism to enhance CD8+T cell activation.