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Macrophage-mediated Immunosurveillance in Cancer

巨噬细胞介导的癌症免疫监视

基本信息

批准号：
9146322
负责人：
Mingye Feng
金额：
$ 17.34万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-18 至 2017-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9146322
关键词：
Agammaglobulinaemia tyrosine kinase Award B-Lymphocytes Binding Blocking Antibodies Blood Circulation CD47 gene Cancer Immunology Science Cell surface Cells Data Development Disseminated Malignant Neoplasm Eating Engraftment Environment Event Excision Fostering Goals Grant Health Hematopoietic Human Immune Immune system Immunologic Monitoring Immunotherapy In Vitro Institutes Investigation Knowledge Laboratories Lead Life Ligand Binding Light Lymphocyte Function Malignant - descriptor Malignant Neoplasms Mediating Methods Modeling Molecular Mus Natural Killer Cells Neoplasm Metastasis Pathway interactions Phagocytosis Phase Play Primary Neoplasm Process Receptor Signaling Regenerative Medicine Regulation Research Research Personnel Research Proposals Research Training Role SHPS-1 protein Signal Pathway Signal Transduction Site Solid Neoplasm Surface Surveillance Program T-Lymphocyte Therapeutic Toll-like receptors Training Universities Up-Regulation Work Writing base calreticulin cancer cell cancer therapy career career development improved in vivo macrophage medical schools neoplastic cell novel prevent programs skills stem cell biology symposium trait tumor tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): This proposal outlines an integrated training and research plan Dr. Mingye Feng will complete during the award period. The overall objective of the research proposal is to understand the underlying mechanism of macrophage-mediated immunosurveillance in cancer development and metastasis. The ability to escape from surveillance by the immune system is regarded as one of the essential hallmarks of cancer cells. While the functions of lymphocytes (T, B and NK cells) in "tumor immunosurveillance" have been studied for decades, the roles of macrophages on tumor cell elimination have only begun to be explored. Recent studies showed that blockade of a "don't eat me" signal CD47 on malignant hematopoietic and various solid tumor cells enabled their phagocytosis by macrophages and prevented their engraftment in mice lacking T, B, and NK cells, indicating a key role of macrophages in tumor surveillance and elimination. While inducing macrophage- mediated immunosurveillance holds considerable promise for the treatment of various cancers, its underlying mechanism remains largely unknown. The proposed research will focus on two fundamental questions: how do macrophages target tumor cells and how do cancer cells develop multiple levels of self-protective mechanisms against macrophages during cancer progression and metastasis? In the research plan, specific aim1 is to understand the molecular mechanism of tumor cell recognition and phagocytosis. Aim1 will define how macrophages present the tumor cell detecting molecules on the cell surface and how these molecules mediate the recognition of target cancer cells. Specific aim2 is focused on the multiple layers of self-protective mechanisms against macrophages developed by cancer cells during the process of metastasis. In the K99 phase, aim1 will be mostly completed, and the in vitro and in vivo selection models will be generated for continued investigation towards aim2 in the R00 phase. The proposed studies should shed light on the basic mechanism of tumor cell immune evasion, and enable the development of novel anticancer therapies exploiting the tumoricidal role of macrophages. The training and research plan will be carried out in Dr. Irving L. Weissman's laboratory at Stanford University School of Medicine. The candidate's immediate career goal is to complete the training in the K99 phase to further improve his scientific knowledge and skills, including performing research, attending conferences and courses, writing grants, presenting research work and managing laboratory, which should prepare him for advancing to independence. The candidate's long-term goal is to become an independent principle investigator and perform research in cancer immunology. The candidate's training and research during the K99 phase will receive full support from Dr. Weissman, Stanford Institute for Stem Cell Biology and Regenerative Medicine, and Stanford School of Medicine, who will provide an outstanding environment to foster his career development towards an independent researcher.

描述（由申请人提供）：本建议书概述了一个综合培训和研究计划，冯明业博士将在奖励期间完成。该研究计划的总体目标是了解巨噬细胞介导的免疫监视在癌症发展和转移中的潜在机制。逃避免疫系统监视的能力被认为是癌细胞的基本标志之一。虽然淋巴细胞（T、B和NK细胞）在“肿瘤免疫监视”中的功能已经研究了几十年，但巨噬细胞在肿瘤细胞消除中的作用才刚刚开始探索。最近的研究表明，阻断恶性造血细胞和各种实体瘤细胞上的“不要吃我”信号CD 47使它们能够被巨噬细胞吞噬，并防止它们在缺乏T、B和NK细胞的小鼠中植入，表明巨噬细胞在肿瘤监视和消除中的关键作用。虽然诱导巨噬细胞介导的免疫监视对于治疗各种癌症具有相当大的希望，但其潜在机制在很大程度上仍然未知。这项研究将集中在两个基本问题上：巨噬细胞如何靶向肿瘤细胞，以及癌细胞如何在癌症进展和转移过程中发展出针对巨噬细胞的多水平自我保护机制？在研究计划中，具体目标1是了解肿瘤细胞识别和吞噬的分子机制。Aim1将定义巨噬细胞如何在细胞表面呈现肿瘤细胞检测分子，以及这些分子如何介导靶癌细胞的识别。特异性aim2集中于癌细胞在转移过程中形成的针对巨噬细胞的多层自我保护机制。在K99阶段，aim 1将大部分完成，并将生成体外和体内选择模型，以便在R00阶段继续研究aim 2。拟议的研究应该阐明肿瘤细胞免疫逃避的基本机制，并使开发新的抗癌疗法利用巨噬细胞的杀肿瘤作用。培训和研究计划将在Dr.欧文L.韦斯曼在斯坦福大学医学院的实验室。候选人的直接职业目标是完成K99阶段的培训，以进一步提高他的科学知识和技能，包括进行研究，参加会议和课程，撰写赠款，介绍研究工作和管理实验室，这应该为他走向独立做好准备。候选人的长期目标是成为一名独立的主要研究者，并在癌症免疫学方面进行研究。候选人在K99阶段的培训和研究将得到韦斯曼博士，斯坦福大学干细胞生物学和再生医学研究所和斯坦福大学医学院的全力支持，他们将提供一个优秀的环境，以促进他的职业发展，成为一名独立的研究人员。