Molecular and Epigenetic Programs Underlying T cell Tolerance to Tumor Antigens

项目摘要/摘要 Andrea Schietinger博士是一位积极进取的基础研究科学家，在肿瘤方面有着深厚的背景 免疫学。Schietinger博士的近期目标是了解T细胞的调节机制(S 自身抗原和肿瘤抗原特异性CD8T细胞的无反应性及评价替代T细胞的策略 改善癌症免疫治疗的细胞固有耐受性计划。 Schietinger博士将使用临床相关的小鼠模型来阐明精确的分子和 表观遗传学程序潜在的T细胞对自身抗原的耐受性(K99获奖期)。从以下方面获得的见解 然后将自我耐受模型应用于新开发的本土实体癌模型，以 了解为什么癌前病变和/或早期肿瘤中的肿瘤特异性T细胞对 癌症(R00获奖期)。其具体目的是：(1)通过对自耐性T细胞表观基因组的定义 对染色质状态进行全面、高分辨率的全基因组分析，并确定耐受性 记忆被编码，(2)评估肿瘤引起的T细胞功能障碍的功能特征，并 确定肿瘤特异性T细胞的功能无反应性是否为印迹分化状态 自我耐受性，以及(3)评估消除功能障碍耐受性T细胞表观遗传记忆的策略 并永久挽救T细胞功能，用于癌症免疫治疗。阐明遗传和表观遗传学 自我耐受、肿瘤免疫等不同环境下T细胞无应答的调节机制(S) 诱导T细胞耐受可能揭示T细胞功能障碍的共同潜在原理并导致新的 癌症和其他T细胞介导的疾病的治疗方法，如自身免疫和慢性 感染。 Schietinger博士将在K99获奖期的指导下进行研究 华盛顿大学免疫学系教授、 免疫学项目，弗雷德·哈钦森癌症研究中心(FHCRC)。格林伯格博士是一位领先的 小鼠和人类肿瘤免疫学领域的研究人员，有成功的跟踪记录 师徒关系。华盛顿大学(UW)和(FHCRC)提供了一个极好的环境 必要的资源，包括基础设施、人员、仪器设备和核心设施，以开展 建议进行的研究。Schietinger博士组建了一个优秀的科学咨询委员会，向她保证 学术进步，并将补充格林伯格博士的指导。委员会成员包括杜兰特博士。 免疫学系(UW)教授迈克尔·贝文(Michael Bevan)； 基因组科学部(UW)；以及FHCRC的成员，包括Stanley Riddell博士，计划 免疫学教授，人类生物学和临床研究部Muneesh Tewari和教授Kim MarGolin 他是西雅图癌症护理联盟黑色素瘤诊所的主任。所有这些成员 都是各自领域的专家，将为她的项目带来更多关于T细胞领域的见解和技术 生物学和T细胞记忆、表观遗传学、微核糖核酸和临床/人类肿瘤免疫学。 从长远来看，Schietinger博士的目标是成为一名拥有独立研究人员的肿瘤免疫学家 利用小鼠模型破译癌细胞和免疫之间复杂相互作用的研究计划 并找到机会利用所获得的洞察力为人类开发更好的治疗方法 癌症。

PROJECT SUMMARY / ABSTRACT Dr. Andrea Schietinger is a motivated basic research scientist with a strong background in tumor immunology. Dr. Schietinger's immediate goals are to understand the regulatory mechanism(s) of T cell unresponsiveness in self-antigen and tumor-antigen specific CD8 T cells and evaluate strategies to override T cell-intrinsic tolerance programs to improve cancer immunotherapy. Dr. Schietinger will use clinically relevant mouse models to elucidate the precise molecular and epigenetic programs underlying T cell tolerance to self-antigens (K99 award period). Insights gained from the self-tolerance model will then be applied to a newly developed autochthonous solid cancer model to understand why tumor-specific T cells in premalignant lesions and/or early tumors become unresponsive to the cancer (R00 award period). The Specific Aims are: (1) To define the self-tolerant T cell epigenome through comprehensive, high-resolution genome-wide analysis of chromatin states and to determine how tolerance memory is encoded, (2) To evaluate the functional characteristics of tumor-induced T cell dysfunction and to determine if functional unresponsiveness of tumor-specific T cells is an imprinted differentiation state similar to self-tolerance, and (3) To evaluate strategies to erase the epigenetic memory in dysfunctional tolerant T cells and to permanently rescue T cell function for cancer immunotherapy. Elucidating the genetic and epigenetic regulatory mechanism(s) of T cell unresponsiveness in different settings such as self-tolerance and tumor- induced T cell tolerance may reveal common underlying principles of T cell dysfunction and lead to new therapeutic approaches for cancer and other T cell-mediated diseases such as autoimmunity and chronic infections. Dr. Schietinger will carry out the research during the mentored K99 award period under the guidance of Dr. Philip Greenberg, Professor in the Department of Immunology, University of Washington, and Head of the Program of Immunology, Fred Hutchinson Cancer Research Center (FHCRC). Dr. Greenberg is a leading researcher in the field of mouse and human tumor immunology with a proven track record of successful mentorship. The University of Washington (UW) and (FHCRC) provide an excellent environment with the necessary resources, including infrastructure, personnel, instrumentation and core facilities, to carry out the proposed studies. Dr. Schietinger has formed an excellent scientific advisory committee that assures her academic progress and will complement Dr. Greenberg's mentorship. The committee members include Drs. Michael Bevan, Professor in the Department of Immunology (UW); John Stamatoyannopulos, Professor in the Department of Genome Sciences (UW); and Members of the FHCRC including Drs. Stanley Riddell, Program of Immunology, Muneesh Tewari, Human Biology and Clinical Research Division, and Kim Margolin, Professor of Medicine (UW) and Head of the Melanoma Clinic at the Seattle Cancer Care Alliance. All of these members are experts in their fields and will bring additional insights and technologies to her project in the areas of T cell biology and T cell memory, epigenetics, microRNA, and clinical/human tumor immunology. In the long-term, Dr. Schietinger's goal is to become a tumor immunologist with an independent research program using mouse models to decipher the complex interplay between cancer cells and immune cells in solid tumors and find opportunities to use the acquired insights to develop better treatments for human cancers.