Spatiotemporal regulation of T cell fate decisions in cancer

癌症中 T 细胞命运决定的时空调控

• 批准号: 9350820
• 负责人: Andrea Schietinger
• 金额: $ 257.85万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9350820
• 关键词: Address; Antigens; Automobile Driving; CD8-Positive T-Lymphocytes; Cancer Cell Growth; Cancer Control; Cells; Chromatin; Development; Excision; Goals; Immune system; Immunosuppressive Agents; Malignant Neoplasms; Maps; Mutate; Normal tissue morphology; Pathologic; Patients; Premalignant; Proteins; Shapes; Signal Transduction; Solid Neoplasm; Stem cells; T cell differentiation; T cell regulation; T-Lymphocyte; Technology; Testing; Tissues; Tumor Antigens; cancer cell; cancer genetics; cancer immunotherapy; clinically relevant; design; epigenome; exhaust; fighting; immunopathology; insight; mouse model; novel; pathogen; spatiotemporal; tumor; tumorigenesis

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.

项目概要 免疫系统具有检测和消除病原体的巨大能力，但要利用这种能力。 事实证明，对抗癌症的一个主要障碍是针对肿瘤特异性（突变）的 CD8 T 细胞。 肿瘤中发现的蛋白质是无反应的，无法消除癌细胞。 被认为是在肿瘤发展后期出现的，因为肿瘤特异性 T 细胞变得“耗尽” 并由于持续的抗原暴露而偏离正常的效应器编程和/或 使用临床相关的遗传癌症小鼠模型，I。 最近证明，肿瘤特异性 T 细胞在癌前分化为无反应状态 阶段，早在病理学定义的肿瘤出现之前，T细胞无反应就不是。 必然在肿瘤发生后期建立，但在初次接触肿瘤后就已经建立 因此，为了重新编程肿瘤特异性T细胞以进行癌症免疫治疗，我们必须超越抗原。 当前肿瘤特异性 T 细胞的框架是“耗尽”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中重新分化为功能状态。 在这个提案中，我计划解决三个关键问题：（1）肿瘤特异性T细胞的命运何时何地 与肿瘤抗原初次接触时收到的信号是否决定了细胞的命运？ 肿瘤切除后不同区室中的肿瘤特异性 T 细胞状态如何演变？ 细胞的命运是固定的，还是会随着肿瘤的切除而进化或改变？（3）我们如何有效地重新编程肿瘤？ 治疗实体瘤的特异性 T 细胞？ 为了实现这一目标，我建议 (i) 绘制时间和细胞图谱。 肿瘤发生过程中影响肿瘤特异性 T 细胞命运决定的空间因素 (ii) 决定可塑性 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 (iii) 利用从干细胞重编程研究中获得的见解以及新颖的表观基因组编辑 重新分化肿瘤特异性 T 细胞的技术将使其能够有效控制癌细胞的生长 不会引起过度的免疫病理学。