The Role of Non-Hematopoietic Cells in Tumor Tolerance Induction

描述（由申请人提供）：候选人目标和职业发展计划：候选人是一名胸外科医生，最终目标是成为肿瘤免疫学领域的独立研究者。尽管最近描述适应性免疫系统对于肿瘤免疫监视和消除是重要的，但临床上明显的肿瘤在具有完整免疫系统的个体中发展并显示肿瘤特异性耐受性。候选人的目标是发展研究肿瘤特异性耐受诱导所需的知识和技能。候选人将在五年内通过以下方式实现这一目标：1）研究非造血基质细胞在肿瘤相关调节性T细胞生成中的作用; 2）评估肿瘤MHC II类表达对肿瘤免疫应答的作用; 3）收集过渡到独立研究所需的数据。 工作环境：圣路易斯华盛顿大学的环境是特殊的，有多名研究人员在免疫学的各个方面都有专业知识。候选人的赞助商是国际公认的肿瘤免疫学专家。他在肿瘤免疫编辑方面的工作在促进对肿瘤免疫监视以及允许肿瘤生长的逃逸机制的理解方面发挥了关键作用。导师的实验室研究肿瘤与适应性免疫系统相互作用的多个方面，是实现候选人目标的理想选择。 研究建议：这项资助的主要目的是评估非造血细胞在肿瘤特异性调节性T细胞生成中的作用。初步数据表明，CD 4 + Foxp 3+调节性T细胞的数量在荷瘤组织内增加，并且一些非造血实质细胞表达表面MHC II类，并且能够摄取、加工和呈递外源抗原给CD 4 + T细胞。基于此以及候选人先前发表的数据，假设实质细胞对肿瘤相关抗原的呈递导致调节性T细胞的产生和肿瘤特异性耐受的诱导。本提案中概述的具体目标侧重于使用多种体外和体内模型评价该假设。这些研究将有助于确定非造血细胞在诱导实体瘤免疫耐受中的作用。

DESCRIPTION (provided by applicant): Candidate Goals and Career Development Plan: The candidate is a thoracic surgeon with the ultimate goal of becoming an independent investigator in the field of tumor immunology. Despite the recent description that the adaptive immune system is important for tumor immune surveillance and elimination, clinically evident tumors develop in individuals with an intact immune system and display tumor specific tolerance. The candidate's goal is to develop the fund of knowledge and skills necessary to study tumor specific tolerance induction. The candidate will achieve this over a period of five years by: 1) studying the role of non-hematopoietic stromal cells in the generation of tumor associated regulatory T cells; 2) evaluating the role of tumor MHC Class II expression on the tumor immune response and; 3) gathering data necessary to transition to independent investigation. Environment: The environment at Washington University in St. Louis is exceptional with multiple investigators with expertise in various aspects of immunology. The candidate's sponsor specifically is an internationally recognized expert in tumor immunology. His work on tumor immunoediting has played a pivotal role in advancing the understanding of tumor immune surveillance as well as escape mechanisms that allow for tumor growth. The mentor's laboratory studies multiple aspects of tumor interaction with the adaptive immune system and is ideal for achieving the candidate's goals. Research Proposal: The primary aim of this grant is to evaluate the role of non-hematopoietic cells in the generation of tumor specific regulatory T cells. Preliminary data indicate that the number of CD4+Foxp3+ regulatory T cells increases within tumor bearing tissues and that some non-hematopoietic parenchymal cells express surface MHC Class II and are able to take up, process, and present foreign antigen to CD4+ T cells. Based on this as well as the candidate's previously published data it is hypothesized that presentation of tumor associated antigen by parenchymal cells leads to the generation of regulatory T cells and induction of tumor specific tolerance. The specific aims outlined in this proposal focus on evaluating this hypothesis using multiple in vitro and in vivo models. These studies will serve to define the role of non-hematopoietic cells in the induction of immunologic tolerance to solid tumors.