Spatiotemporal regulation of T cell fate decisions in cancer

项目总结 免疫系统具有检测和清除病原体的巨大能力；然而，利用这种能力 事实证明，抗击癌症具有挑战性。一个主要的障碍是肿瘤特异性的CD8T细胞(突变) 在肿瘤中发现的蛋白质是无反应的，无法消除癌细胞。这种非响应状态 一直被认为出现在肿瘤发展的晚期，因为肿瘤特异性T细胞变得“耗尽” 并通过持续的抗原暴露和/或 免疫抑制微环境因素。使用临床相关的遗传性癌症小鼠模型，我 最近证实，肿瘤特异性T细胞在癌前阶段分化为无反应状态 在病理明确的肿瘤出现之前很久就进入了这个阶段。因此，T细胞无反应性不是 在肿瘤发生的后期，但在最初遇到肿瘤之后就已经建立了 抗原。因此，要将肿瘤特异性T细胞重新编程用于癌症免疫治疗，我们必须着眼于 目前肿瘤特异性T细胞的框架是“疲惫的”效应器，需要重新激活，而不是 设计策略，将肿瘤特异性T细胞从无反应的命运重新分化为功能状态。在……里面 在这项提议中，我计划解决三个关键问题：(1)肿瘤特异性T细胞何时何地死亡 做了什么决定？在最初接触肿瘤抗原时收到的信号决定细胞命运吗？(2) 肿瘤切除后不同间隔内的肿瘤特异性T细胞状态是如何演变的？是肿瘤特异性T细胞 细胞命运是固定的，还是会随着肿瘤的切除而进化或改变？(3)我们如何有效地对肿瘤进行重新编程- 用于实体瘤治疗的特异性T细胞？为了实现这一目标，我建议(I)绘制时间和 在肿瘤发生过程中决定肿瘤特异性T细胞命运的空间因素(II)决定可塑性 肿瘤切除前后不同组织中肿瘤特异性T细胞的染色质状态 以及(Iii)使用从干细胞重新编程研究中获得的见解以及新的表观基因组编辑 重新分化肿瘤特异性T细胞的技术，使它们能够有效地控制癌细胞生长 而不会引起过度的免疫病理反应。

PROJECT SUMMARY The immune system has enormous power to detect and eliminate pathogens; however, harnessing this power to fight cancer has proven challenging. A major barrier is that CD8 T cells specific for tumor-specific (mutated) proteins and found in tumors are non-responsive and fail to eliminate cancer cells. This non-responsive state has been thought to arise late during tumor development because tumor-specific T cells become “exhausted” and derailed from their normal effector programming by persistent antigen exposure and/or immunosuppressive microenvironmental factors. Using clinically-relevant genetic cancer mouse models, I recently demonstrated that tumor-specific T cells differentiate to a non-responsive state at the pre-malignant stage, long before the emergence of a pathologically-defined tumor. Thus, T cell non-responsiveness is not necessarily established late during tumorigenesis, but instead already after the initial encounters with tumor antigen. Therefore, to reprogram tumor-specific T cells for cancer immunotherapy, we must look beyond the current framework of tumor-specific T cells as “exhausted” effectors that need to be re-invigorated and instead design strategies to re-differentiate tumor-specific T cells out of the non-responsive fate to a functional state. In this proposal, I plan to address three critical questions: (1) When and where are tumor-specific T cells fate decisions made? Do signals received during the initial encounter with tumor antigen determine cell fates? (2) How do tumor-specific T cell states in different compartments evolve after tumor resection? Is tumor-specific T cells fate fixed, or can it evolve or change with tumor removal? (3) How can we effectively reprogram tumor- specific T cells for the treatment of solid tumors? To achieve this goal, I propose to (i) map the temporal and spatial factors shaping tumor-specific T cells fate decisions during tumorigenesis (ii) determine the plasticity and chromatin states of tumor-specific T cells in different tissue compartments before and after tumor resection and (iii) use insights gained from stem cell reprogramming studies together with novel epigenome editing technology to re-differentiate tumor-specific T cells that will allow them to effectively control cancer cell growth without inducing excessive immunopathology.