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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：
10683723
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/10683723
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 Board Certification 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 Education Environment Gene Expression Profile 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 Interferon Type II Internal Medicine Laboratories Lead Lesion LoxP-flanked allele Lung Lung Adenocarcinoma Macrophage 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 Population Principal Investigator Program Development Proteins Regimen Regulation Research Personnel Research Project Grants Resolution 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 antigen-specific T cells bak protein cancer cell cancer immunobiology cancer immunotherapy career development cell transformation cell type checkpoint therapy clinical training 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 metaplastic cell transformation monocyte mortality mouse model neoantigens neoplastic cell novel pathogen patient subsets prevent programmed cell death protein 1 recruit response restraint sarcoma single-cell RNA sequencing skill acquisition 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.

项目总结/摘要该提案的长期目标是培养申请人成为一名独立的学术医生- 科学家研究自然和治疗免疫反应对肺癌。主要研究者 (PI)曾获得免疫学博士学位培训，以及内科临床培训，血液学/肿瘤学。他是ABIM委员会认证的医学肿瘤学。本申请描述了一个为期5年的职业发展计划，将为PI提供指导教育经验，目的是在分子分析，高维分析，计算生物学，和人肺腺癌的小鼠模型。在奖励期结束时，PI将获得了必要的技能，以实现他的最终目标，成为一个独立的调查员，研究肺癌免疫生物学和免疫疗法的学术医疗中心，并照顾患者胸部恶性肿瘤该研究项目将利用的专业知识和环境华盛顿大学在培养和支持医学科学家方面有着悠久的历史。博士 Robert D. Schreiber将指导PI的科学和职业发展。施赖伯博士的工作 “免疫编辑假说”以及证明免疫基因组学方法能够识别癌症新抗原，即由恶性肿瘤特征的基因组不稳定性引起的改变的蛋白质，并将其作为有效的个性化癌症疫苗的基础。一个科学家咨询委员会将提供更多的科学和职业指导。肺癌是最常见的癌症相关的原因全世界的死亡率。新的免疫治疗方法对转移性乳腺癌患者的一个子集有益肺腺癌（LUAD），最常见的非小细胞肺癌亚型，但反应是往往不耐用。LUAD的组织微环境特征为肿瘤相关的细胞系，巨噬细胞（TAM），其抑制T细胞应答。我们的实验室已经证明，TAM显示出一系列的激活状态，从主要的抗炎表型，逐渐在对免疫疗法有反应的肿瘤中，治疗在这个提议中，我们将检验T细胞依赖性和肿瘤细胞内在性的假设，信号是TAM募集到LUAD微环境中所必需的，并且癌症新抗原由TAM呈现的免疫调节决定了由癌症免疫疗法动员的T细胞的肿瘤内功能。为在这些研究中，我们将利用一种表达癌症的人类LUAD的基因工程小鼠模型，我们实验室先前鉴定和表征的新抗原。这使我们能够评估免疫对早期和转移性癌症的反应。准确的种群鉴定抑制抗肿瘤免疫应答的TAM将具有临床相关意义，为非小细胞肺癌患者开发新的免疫疗法。