Molecular and Epigenetic Programs Underlying T cell Tolerance to Tumor Antigens

描述（由申请人提供）：Andrea Schietinger博士是一位积极的基础研究科学家，在肿瘤免疫学方面具有很强的背景。Schietinger博士的近期目标是了解自身抗原和肿瘤抗原特异性CD 8 T细胞中T细胞无反应性的调节机制，并评估超越T细胞内在耐受性程序以改善癌症免疫治疗的策略。Schietinger博士将使用临床相关的小鼠模型来阐明T细胞对自身抗原耐受性的精确分子和表观遗传程序（K99奖期）。从自身耐受模型中获得的见解将应用于新开发的本地实体癌模型，以了解为什么癌前病变和/或早期肿瘤中的肿瘤特异性T细胞对癌症无反应（R 00奖励期）。具体目标是：（1）通过对染色质状态进行全面的、高分辨率的全基因组分析来定义自身耐受性T细胞表观基因组，并确定耐受性记忆是如何编码的，（2）评估肿瘤诱导的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是类似于自身耐受性的印记分化状态，以及（3）评估消除功能障碍的耐受性T细胞中的表观遗传记忆并永久拯救T细胞功能用于癌症免疫治疗的策略。阐明T细胞在不同环境中无反应性的遗传和表观遗传调节机制，如自身耐受性和肿瘤诱导的T细胞耐受性，可以揭示T细胞功能障碍的共同基本原理，并导致癌症和其他T细胞介导的疾病，如自身免疫和慢性感染的新治疗方法。Schietinger博士将在华盛顿大学免疫学系教授、Fred哈钦森癌症研究中心（FHCRC）免疫学项目负责人Philip Greenberg博士的指导下，在指导K99奖期间开展研究。Greenberg博士是小鼠和人类肿瘤免疫学领域的领先研究人员，拥有成功指导的良好记录。华盛顿大学（UW）和（FHCRC）提供了一个良好的环境和必要的资源，包括基础设施，人员，仪器和核心设施，以开展拟议的研究。Schietinger博士组建了一个优秀的科学咨询委员会，确保她的学术进步，并将补充格林伯格博士的指导。委员会成员包括免疫学系（UW）教授Michael Bevan博士;基因组科学系（UW）教授John Stamatoyannopulos;以及FHCRC的成员，包括免疫学计划的Stanley里德尔博士，人类生物学和临床研究部的Muneesh Tewari博士，以及医学教授（UW）兼西雅图癌症护理联盟黑色素瘤诊所负责人Kim Margolin博士。所有这些成员都是各自领域的专家，并将为她在T细胞生物学和T细胞记忆，表观遗传学，microRNA和临床/人类肿瘤免疫学领域的项目带来更多的见解和技术。从长远来看，Schietinger博士的目标是成为一名肿瘤免疫学家，拥有一个独立的研究项目，使用小鼠模型来破译实体瘤中癌细胞和免疫细胞之间复杂的相互作用，并找到机会利用获得的见解来开发更好的人类癌症治疗方法。

DESCRIPTION (provided by applicant): 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 evaluae 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.