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

肿瘤相关巨噬细胞的癌细胞和 T 细胞依赖性调节

基本信息

批准号：
10015239
负责人：
Jeffrey P Ward
金额：
$ 19.82万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-10 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10015239
关键词：
Academic Medical Centers Adaptive Immune System Address Advisory Committees Anti-Inflammatory Agents Antibodies Antigen Presentation Antigens Antitumor Response Autoimmunity Award Blood Vessels CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CDKN2A gene CTLA4 gene Cancer Etiology Cancer Vaccines Cell division Cells Characteristics Clinical Computational Biology Cytometry Cytotoxic Chemotherapy DNA Sequence Alteration Dendritic Cells Development Disseminated Malignant Neoplasm Environment Genetic Transcription Genetically Engineered Mouse Genomic Instability Goals Granulocytic Sarcoma Growth Growth Factor Hematology Histocompatibility Antigens Class II Homeostasis Hyperplasia Immune Targeting Immune response Immune system Immunogenomics Immunologics Immunology Immunosuppression Immunotherapeutic agent Immunotherapy Induced Mutation Infiltration Inflammatory Interferons Internal Medicine Investigation Laboratories Lead Lesion Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of thorax Mediating Medical Oncology Mentors Methylcholanthrene Modeling Molecular Profiling Monoclonal Antibodies Mus Mutation Myelogenous Myeloid Cells Myeloid-derived suppressor cells Non-Small-Cell Lung Carcinoma Oncogenic Oncology Patient Care Patients Peptides Phenotype Physicians Play Population Principal Investigator Program Development Proteins Regimen Regulation Research Personnel Research Project Grants Resolution Role STK11 gene Scientist Signal Transduction Surface T cell response T-Cell Activation T-Lymphocyte Testing Tissues Training Transplantation Treatment Efficacy Tumor Immunity Tumor-Infiltrating Lymphocytes Tumor-associated macrophages Universities Vocational Guidance Washington Work adenoma anti-CTLA4 anti-PD-1 anti-tumor immune response bak protein cancer cell cancer immunobiology cancer immunotherapy career development cell transformation cell type checkpoint therapy clinically relevant cytokine dimensional analysis early phase clinical trial effector T cell exhaustion experience genetic regulatory protein high dimensionality human model immune checkpoint improved individual patient longitudinal analysis lung development macrophage metaplastic cell transformation monocyte mortality mouse model neoantigens neoplastic cell novel pathogen patient subsets prevent programmed cell death protein 1 recruit response sarcoma single-cell RNA sequencing skills therapy resistant tumor tumor growth tumor microenvironment

项目摘要

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.

项目摘要/摘要该提案的长期目标是培训申请人成为一名独立的学术医师 - 科学家研究针对肺癌的天然和治疗性免疫反应。首席研究员（PI）以前已经获得了免疫学博士培训，以及内科和血液学/肿瘤学。他在医学肿瘤学中获得了Abim董事会的认证。该申请描述了5年职业发展计划将为PI提供教育经验，目的在分子分析，高维分析，计算生物学方面发展新的科学专业知识，和人肺腺癌的小鼠模型。在颁奖期结束时，PI将有获得了实现他成为成为独立研究者的最终目标所必需的技能研究肺癌免疫生物学和免疫疗法的学术医学中心，并照顾患者有胸腔恶性肿瘤。该研究项目将利用华盛顿大学（Washington University）有着长期发展和支持身体科学家的记录。博士罗伯特·施雷伯（Robert D. Schreiber）将指导PI的科学和职业发展。 Schreiber博士的工作负责对于“免疫编辑假设”，以及免疫基因组学方法的证明鉴定癌症新抗原，这是由于恶性肿瘤的基因组不稳定性特征而改变的蛋白质，并将其作为有效个性化癌症疫苗的基础。科学家咨询委员会将提供其他科学和职业指导。肺癌是癌症相关的最常见原因全球死亡率。新型免疫疗法方法对转移性患者的一部分有益肺腺癌（LUAD）是非小细胞肺癌最常见的亚型，但反应是通常不耐用。 LUAD的组织微环境的特征是肿瘤相关的谱系巨噬细胞（TAM），它抑制了T细胞反应。我们的实验室证明了TAM显示激活状态的光谱范围从逐渐逐渐抗炎表型在肿瘤中，将肿瘤生长为主要促炎表型的肿瘤，对免疫疗法有反应治疗。在此提案中，我们将测试T细胞依赖性和肿瘤细胞中心的假设 TAM募集到LUAD微环境中需要信号，并且癌症新抗原剂由TAM提出，确定了由癌症免疫疗法动员的T细胞的肿瘤内功能。为了这些研究，我们将利用一种表达癌症的人类LUAD的一般设计的小鼠模型新抗原先前以我们的实验室为特征。这使我们能够评估免疫对早期和转移性癌症的反应。确定的确切人群 TAM认为，约束抗肿瘤免疫反应将对非小细胞肺癌患者的新型免疫疗法开发。