Targeting mTOR for Immunity to Cancer

描述（由申请人提供）：癌症影响所有年龄的人，但发展这种疾病的大多数形式的风险随着年龄的增长而增加。免疫系统如何随年龄变化以及这对癌症发展或控制的影响尚不完全清楚。然而，我们确实知道，一般来说，CD8 T细胞在对癌症的免疫中起着至关重要的作用。在活化后，CD8 T细胞经历可预测的发育程序，其特征在于不同的阶段，包括首先扩增，然后收缩，Ag特异性效应物（TE）群体，然后是长寿命记忆细胞（TM）的持久性。由于长寿命的CD8 TM细胞介导对癌症重建的保护性免疫，这些细胞的产生和维持的机制仍然是临床干预的高度期望的靶点。我们以前的工作表明，在免疫应答期间，CD8 T细胞中线粒体脂肪酸氧化（FAO）的促进，这是一种为TCA循环提供燃料的脂质催化剂途径，对于它们发育为长寿的TM细胞至关重要。我们发现哺乳动物雷帕霉素靶蛋白（mTOR）在这一过程中起着核心作用，并利用这一发现来增强疫苗接种后CD8 TM的发育。这一提议扩展了我们的新概念，即细胞代谢调节CD8 TM的发展，mTOR通路调节这一过程。基于我们的观察和一组支持性初步数据，我们假设1）mTOR抑制剂促进CD8 TM细胞的发育，从而保护免受癌症的侵害，2）mTOR通过调节这些细胞中的代谢来控制这一过程。这些研究的长期目标是促进癌症免疫疗法的发展。

DESCRIPTION (provided by applicant): Cancer affects people of all ages, but the risk of developing most forms of this disease increases with age. How the immune system changes with age and the effect that this has on the development or control of cancer is not completely clear. However we do know that, in general, CD8 T cells play a crucial role in immunity to cancer. Upon activation, CD8 T cells undergo a predictable developmental program characterized by distinct phases encompassing first the expansion, and then contraction, of Ag-specific effector (TE) populations, followed by the persistence of long-lived memory cells (TM). Since long-lived CD8 TM cells mediate protective immunity to the re-establishment of cancer, the mechanisms underlying the generation and maintenance of these cells remain a highly desirable target for clinical intervention. Our previous work has revealed that the promotion of mitochondrial fatty acid oxidation (FAO), a pathway of lipid catabolism that fuels the TCA cycle, in CD8 T cells during an immune response is crucial to their development into long-lived TM cells. We found that the mammalian target of rapamycin (mTOR) plays a central role in this process and exploited this finding to enhance CD8 TM development after vaccination. This proposal extends our novel concept that cellular metabolism regulates the development of CD8 TM and that the mTOR pathway modulates this process. Based on our observations, and a panel of supportive preliminary data, we hypothesize that 1) inhibitors of mTOR promote the development of CD8 TM cells that protect against cancer, and 2) mTOR controls this process by regulating metabolism in these cells. The long-term goal of these studies is to facilitate the development of immunotherapies against cancer.