Targeting mTOR for Immunity to Cancer

描述(申请人提供)：癌症影响所有年龄段的人，但发展为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的发展或控制的影响尚不完全清楚。然而，我们确实知道，总的来说，CD8T细胞在抗癌免疫中起着至关重要的作用。在激活后，CD8T细胞经历了一个可预测的发育程序，其特征是经历了不同的阶段，首先是Ag特异性效应(TE)群体的扩张，然后是收缩，然后是长寿命记忆细胞(TM)的持续。由于长寿命的CD8TM细胞介导了对癌症重建的保护性免疫，因此这些细胞的产生和维持的机制仍然是临床干预的高度理想的靶点。我们以前的工作表明，在免疫应答过程中，促进CD8T细胞线粒体脂肪酸氧化(FAO)，这是一种促进TCA循环的脂质分解代谢途径，对它们发育成长期存活的TM细胞至关重要。我们发现哺乳动物的雷帕霉素靶标(MTOR)在这一过程中发挥了核心作用，并利用这一发现促进了免疫后CD8 TM的发育。这一建议扩展了我们的新概念，即细胞代谢调节CD8TM的发育，mTOR途径调节这一过程。基于我们的观察和一组支持性的初步数据，我们假设1)mTOR的抑制剂促进CD8 TM细胞的发展，从而预防癌症，2)mTOR通过调节这些细胞的新陈代谢来控制这一过程。这些研究的长期目标是促进抗癌免疫疗法的发展。 公共卫生相关性：我们的建议扩展了我们最近的新发现，表明细胞新陈代谢调节免疫记忆的发展，mTOR途径调节这一过程。我们将确定mTOR如何调节免疫细胞的新陈代谢，并确定传统上因其直接抗肿瘤特性而被用于治疗癌症的mTOR抑制剂是否真的能促进肿瘤特异性免疫记忆，从而预防癌症。

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. PUBLIC HEALTH RELEVANCE: Our proposal extends our recent novel findings demonstrating that cellular metabolism regulates the development of immunological memory, and that the mTOR pathway modulates this process. We will establish how mTOR regulates metabolism in immune cells and determine whether mTOR inhibitors, which have traditionally been used to treat cancer for their direct anti-tumor properties, can actually promote tumor-specific immunological memory and thereby protect against cancer.