Spatiotemporal regulation of T cell fate decisions in cancer

项目摘要 免疫系统有巨大的力量来检测和消除病原体;然而，利用这种力量， 对抗癌症已经被证明是具有挑战性的。一个主要的障碍是对肿瘤特异性（突变） 在肿瘤中发现的蛋白质是无反应的，不能消除癌细胞。这种无反应状态 被认为在肿瘤发展的后期出现，因为肿瘤特异性T细胞变得“耗尽”， 并且通过持续的抗原暴露而偏离其正常的效应物编程，和/或 免疫抑制微环境因素。使用临床相关的遗传癌症小鼠模型，我 最近证明，肿瘤特异性T细胞在癌前病变时分化为非应答状态， 阶段，早在病理学定义的肿瘤出现之前。因此，T细胞无反应性不是 在肿瘤发生的后期，这些蛋白质必然建立，但在最初遇到肿瘤后就已经建立了。 抗原的因此，为了重新编程肿瘤特异性T细胞用于癌症免疫治疗，我们必须超越肿瘤特异性T细胞。 肿瘤特异性T细胞作为“耗尽”效应子的当前框架需要重新激活， 设计策略以将肿瘤特异性T细胞从非应答性命运重新分化为功能状态。在 在这个提议中，我计划解决三个关键问题：（1）肿瘤特异性T细胞的命运是何时何地 做出的决定？在最初遇到肿瘤抗原时收到的信号决定细胞的命运吗？（二） 肿瘤切除术后不同区室中的肿瘤特异性T细胞状态如何演变？是肿瘤特异性T细胞 细胞的命运是固定的，还是随着肿瘤的切除而进化或改变？(3)我们如何有效地重新编程肿瘤- 特异性T细胞用于治疗实体瘤？为了实现这一目标，我建议（一）映射时间和 在肿瘤发生过程中塑造肿瘤特异性T细胞命运决定的空间因素（ii）决定了可塑性 肿瘤切除前后不同组织区室中肿瘤特异性T细胞的染色质状态 和（iii）使用从干细胞重编程研究中获得的见解以及新的表观基因组编辑 一种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的生长 而不引起过度的免疫病理学。

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.