Metabolic reprogramming of Tregs in tumor immunity

程序描述/摘要 代谢重编程是癌细胞生长和激活的一个基本过程 淋巴细胞。这些快速分裂的细胞显著上调有氧糖酵解(Warburg新陈代谢)和 还重新编程线粒体氧化磷酸化(OXPHOS)以支持能量和生长 要求。此外，mTOR信号是癌细胞合成代谢的中心调节器，并且 淋巴细胞。在积极研究Warburg和线粒体新陈代谢和mTOR信号的同时，我们 才刚刚开始意识到其他生物合成程序的参与，如从头合成脂肪 (脂肪生成)。新出现的证据表明，癌症免疫疗法是抗击癌症的有力工具， 但免疫抑制调节性T细胞(Tregs)介导的免疫耐受是一个主要障碍 有效的抗肿瘤免疫。尽管mTOR通常被认为是一种至关重要的负面调节因素 Tregs，我们的遗传学研究表明，mTORC1是Treg功能的关键正决定因素，通过 将免疫信号与造脂程序联系起来。在我们的初步研究中，脂肪生成程序的中断 在Tregs的作用下，小鼠能够排斥肿瘤细胞，但在稳定状态下没有引起明显的自身免疫紊乱 州政府。我们假设生脂程序有助于肿瘤中的Treg抑制活性。 微环境，这可能是癌症免疫治疗的新靶点。我们将检验这一假设 通过确定Treg造脂程序在肿瘤免疫中的作用，并确定代谢和 信号基础，脂肪生成据此编程Treg功能。我们预测这些研究将建立一个新的 我们理解Tregs的造脂程序以及这如何影响肿瘤免疫的范例。 从这个项目中获得的见解可能会导致癌症免疫治疗的创新战略 利用Tregs的新陈代谢重新编程。

Program Description/Abstract Metabolic reprogramming is a fundamental process underlying the growth of cancer cells and activated lymphocytes. These rapidly dividing cells markedly upregulate aerobic glycolysis (Warburg metabolism) and also reprogram mitochondrial oxidative phosphorylation (OXPHOS) to support the energy and growth demands. Moreover, mTOR signaling is a central regulator of anabolic metabolism in cancer cells and lymphocytes. While Warburg and mitochondrial metabolism and mTOR signaling are being actively studied, we are just beginning to appreciate the involvement of other biosynthetic programs such as de novo lipid synthesis (lipogenesis). Emerging evidence highlights that cancer immunotherapy is a powerful tool to combat cancers, but immune tolerance mediated by immunosuppressive regulatory T cells (Tregs) represents a major obstacle for effective anti-tumor immunity. Although mTOR was generally considered a crucial negative regulator of Tregs, our genetic studies have revealed that mTORC1 is a pivotal positive determinant of Treg function by linking immune signals to the lipogenic program. In our preliminary studies, disruption of the lipogenic program in Tregs rendered the mice to reject tumor cells but did not cause obvious autoimmune disorders under steady state. We hypothesize that lipogenic program contributes to Treg suppressive activity in the tumor microenvironment, which could represent a novel target for cancer immunotherapy. We will test this hypothesis by establishing the roles of Treg lipogenic programs in tumor immunity, and determining the metabolic and signaling basis whereby lipogenesis programs Treg functions. We predict these studies will establish a new paradigm on our understanding of lipogenic program in Tregs and how this impinges upon tumor immunity. Insights gained from this project will likely lead to innovative strategies on cancer immunotherapy by capitalizing on metabolic reprogramming of Tregs.