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

在肠肿瘤发生模型中，我们最近发现STAT3的缺失导致肠上皮细胞（IEC）的有丝分裂升高，进而导致溶酶体膜渗透（LMP），从而增强抗原呈递和CD8+ T细胞的活化。在本提案中，我们计划定义触发线粒体自噬的分子机制，并筛选随后启动LMP的线粒体自噬诱导剂。此外，我们将评估线粒体自噬和LMP诱导是否能够使已建立的肿瘤对检查点抑制敏感，并将研究线粒体自噬和LMP诱导是否代表了增强CD8+T细胞活化的共同机制。

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.