Cancer-Cell and T-cell Dependent Regulation of Tumor Associated Macrophages

项目摘要/摘要 这项建议的长期目标是培训申请者成为一名独立的、学术的医生- 研究针对肺癌的自然和治疗性免疫反应的科学家。首席调查员 (PI)此前曾接受免疫学博士培训，以及内科和临床培训 血液学/肿瘤学。他是ABIM董事会认证的内科肿瘤学专家。这份申请描述了一个5年期的 职业发展计划，将为PI提供有指导的教育经验，目的是 在分子图谱、高维分析、计算生物学、 以及人类肺腺癌的小鼠模型。在授权期结束时，PI将拥有 获得了必要的技能，以实现他的最终目标，成为一名独立的调查员 学术医学中心，研究肺癌免疫生物学和免疫治疗，并照顾患者 患有胸部恶性肿瘤。这项研究项目将利用 华盛顿大学在培养和支持内科科学家方面有着长期的记录。Dr。 Robert D.Schreiber将指导PI的科学和职业发展。Schreiber博士的工作是负责的 “免疫编辑假说”，以及免疫基因组学方法能够 确定癌症新抗原，即由恶性肿瘤的基因组不稳定特征引起的改变蛋白， 并将其作为有效的个性化癌症疫苗的基础。由科学家组成的顾问委员会将 提供额外的科学和职业指导。肺癌是与癌症相关的最常见的原因 全球范围内的死亡率。新的免疫治疗方法对部分转移性患者有益 肺腺癌(LUAD)，非小细胞肺癌最常见的亚型，但反应如下 通常不耐用。LUAD的组织微环境以肿瘤相关谱系为特征 巨噬细胞()，抑制T细胞反应。我们实验室已经证明展示了一种 激活状态的范围从以抗炎为主的表型逐渐变化 对免疫治疗有反应的肿瘤生长为以促炎表型为主的肿瘤 治疗。在这项提议中，我们将检验T细胞依赖和肿瘤细胞固有的假设 重新进入LUAD微环境需要信号，而癌症新抗原 的研究报告确定了癌症免疫疗法动员的T细胞在肿瘤内的功能。为 在这些研究中，我们将利用表达癌症的人类LUAD的基因工程小鼠模型 我们实验室以前发现并鉴定了新的抗原。这使我们能够评估免疫力 对早期和转移性癌症的反应。白纹伊蚊精确种群的鉴定 关于抑制抗肿瘤免疫反应的研究将具有临床意义 为非小细胞肺癌患者开发新的免疫疗法。

PROJECT SUMMARY/ABSTRACT The long-term goal of this proposal is to train the applicant to become an independent, academic physician- scientist studying natural and therapeutic immune responses against lung cancer. The principal investigator (PI) has previously obtained Ph.D training in immunology, as well as clinical training in internal medicine and hematology/oncology. He is ABIM board-certified in medical oncology. This application describes a 5-year career development program that will provide the PI a mentored educational experience with the aim of developing new scientific expertise in molecular profiling, high-dimensional analysis, computational biology, and mouse models of human lung adenocarcinoma. At the conclusion of the award period, the PI will have acquired the skills necessary to achieve his ultimate goal of becoming an independent investigator in a academic medical center studying lung cancer immunobiology and immunotherapy, and caring for patients with thoracic malignancies. This research project will capitalize on the expertise and environment of Washington University, which has a long-track record of developing and supporting physician-scientists. Dr. Robert D. Schreiber will mentor the PI's scientific and career development. Dr. Schreiber's work is responsible for the “immunoediting hypothesis” as well as the demonstration that an immunogenomics approach is able to identify cancer neoantigens, altered proteins resulting from the genomic instability characteristic of malignancy, and use them as a basis for effective personalized cancer vaccines. An advisory committee of scientists will provide additional scientific and career guidance. Lung cancer is the most common cause of cancer-related mortality worldwide. Novel immunotherapy approaches are beneficial for a subset of patients with metastatic lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer, but responses are often not durable. The tissue microenvironment of LUAD is characterized by lineages of tumor-associated macrophages (TAM), which suppress T-cell responses. Our laboratory has demonstrated that TAM display a spectrum of activation states ranging from a predominantly anti-inflammatory phenotype in progressively growing tumors to a predominantly pro-inflammatory phenotype in tumors that respond to immunotherapy treatment. In this proposal, we will test the hypothesis that both T-cell dependent and tumor cell-intrinsic signals are required for TAM recruitment into the LUAD microenvironment, and that cancer neoantigens presented by TAM determine the intratumoral function of T-cells mobilized by cancer immunotherapies. For these studies, we will utilize a genetically engineered mouse model of human LUAD that expresses cancer neoantigens previously identified and characterized by our laboratory. This allows us to assess immune responses against both early stage and metastatic cancers. The identification of the precise populations of TAM that constrain anti-tumoral immune responses will have clinically relevant implications with respect to the development of novel immunotherapies for patients with non-small cell lung cancer.