Elucidating the Regulation and Requirement of the NAD salvage pathway in CD8+ T Cell Exhaustion

项目摘要 基于检查点的癌症免疫疗法的发展在过去已经彻底改变了癌症治疗。 十年尽管许多其他无法治疗的患者已经从这些疗法中获得了长期益处， 对大多数患者的长期益处很小，这突出了对改进治疗的需要。的一个主要目标 基于检查点的疗法是重新激活慢性刺激的、“耗尽的”CD 8 + T细胞以杀死肿瘤。 同样，彻底了解这些长期刺激的细胞和它们的复苏相比， 急性刺激的效应CD 8 + T细胞将继续是未来治疗发现所必需的。它有 越来越多地认识到，除了表观遗传和转录变化，细胞代谢 在促进和决定T细胞命运中起关键作用。然而，特定的代谢要求， 在基于检查点的治疗之前和之后耗尽的CD 8 + T细胞仍然不清楚。我的初步研究 提示NAD补救途径是T细胞活化和分化的新介质， 可以在检查点阻断的情况下进行治疗。我的数据显示，1）NAD 补救途径在CD 8 + T细胞中通过刺激TCR和CD 28来调节，TCR和CD 28的信号传导 已知驱动细胞命运决定; 2）NAD补救途径在整个细胞周期中是不同需要的。 初始CD 8 + T细胞的活化。在T细胞从静止期退出期间，限速酶的活性， NAMPT是细胞存活、增殖和功能所必需的，但不是之后。因此，我假设， NAD补救途径在慢性与急性的背景下受到不同的调节和需要 抗原刺激在这个建议中，我试图通过阐明特定的信号来解决这个假设。 在CD 8 + T细胞中诱导这一途径的机制（Aim 1），并确定这一途径是如何调节的 在用尽情况下（目标2）。这些目标的完成将阐明不同的CD 8 + T 细胞亚群调节并需要NAD补救途径，并将机械地告知未来的设计。 免疫疗法旨在重振耗尽的T细胞。

Project Summary The development of checkpoint based cancer immunotherapy has revolutionized cancer treatment in the last decade. Although many otherwise untreatable patients have seen long term benefit from these therapies, the long-term benefit for most patients is minimal, highlighting a need for improved treatments. A major goal of checkpoint based therapies is to reinvigorate chronically stimulated, “exhausted” CD8+ T cells to kill the tumor. Likewise, a thorough understanding of these chronically stimulated cells and their reinvigoration as compared to acutely stimulated effector CD8+ T cells will continue to be necessary for future therapeutic discovery. It has increasingly become appreciated that in addition to epigenetic and transcriptional changes, cell metabolism plays a critical role in facilitating and determining T cell fate. However, the specific metabolic requirements for exhausted CD8+ T cells before and after checkpoint based treatment remain unclear. My preliminary studies suggest that the NAD salvage pathway is a novel mediator of T cell activation and differentiation, which could be leveraged therapeutically in the context of checkpoint blockade. My data shows that 1) the NAD salvage pathway is regulated in CD8+ T cells through stimulation of both the TCR and CD28, whose signaling is known to drive cell fate determination; 2) The NAD salvage pathway is differentially required throughout the activation of naive CD8+ T cells. During the T cell exit from quiescence, activity of the rate limiting enzyme, NAMPT, is required for cell survival, proliferation, and function, but not after. I thus hypothesize that that the NAD salvage pathway is differentially regulated and required in the context of chronic versus acute antigen stimulation. In this proposal I seek to address this hypothesis by elucidating the specific signaling mechanisms that induce this pathway in CD8+ T cells (Aim 1) and determining how this pathway is regulated and required in the context of exhaustion (Aim 2). Completion of these aims will elucidate how different CD8+ T cell subsets regulate and require the NAD salvage pathway and will mechanistically inform the design of future immunotherapies designed to reinvigorate exhausted T cells.