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（由适用提供）：该提案概述了Mingye Feng博士在奖励期内完成的综合培训和研究计划。研究建议的总体目标是了解巨噬细胞介导的免疫监视在癌症发育和转移中的基本机制。免疫系统摆脱监视的能力被认为是癌细胞的重要标志之一。虽然已经研究了淋巴细胞（T，B和NK细胞）在“肿瘤免疫监测”中的功能数十年，但巨噬细胞在消除肿瘤细胞中的作用才开始探索。最近的研究表明，“不要吃我”的封锁信号CD47在恶性造血和各种实体瘤细胞上的封锁可以通过巨噬细胞吞噬吞噬作用，并防止了他们在缺乏T，B和NK细胞的小鼠中植入它们，这表明巨噬细胞在肿瘤监测和消除中的关键作用。虽然诱导的巨噬细胞介导的免疫监视对各种癌症的治疗有很大的希望，但其潜在机制仍然很少知道。拟议的研究将重点介绍两个基本问题：巨噬细胞如何靶向肿瘤细胞，癌细胞如何在癌症进展和转移过程中发展出多种水平针对巨噬细胞的自我保护机制？在研究计划中，特定的目标是了解肿瘤细胞识别和吞噬作用的分子机制。 AIM1将定义巨噬细胞如何呈现细胞表面上分子的肿瘤细胞，以及这些分子中位数如何识别靶癌细胞的中位数。特定的AIM2集中在转移过程中癌细胞开发的巨噬细胞的多层自我保护机制上。在K99阶段，AIM1将大部分完成，并且将生成体外和体内选择模型以进行持续投资。在R00阶段AIM2。拟议的研究应阐明肿瘤细胞免疫进化的基本机制，并能够开发利用巨噬细胞的结核性作用的新型抗癌疗法。培训和研究计划将在斯坦福大学医学院的欧文·韦斯曼博士实验室中进行。候选人的直接职业目标是在K99阶段完成培训，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，撰写补助金，介绍研究工作和管理实验室，这应该为他促进独立做好准备。候选人的长期目标是成为独立的首席研究员，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获得魏斯曼博士，斯坦福大学干细胞生物学和再生医学研究所以及斯坦福大学医学院的全力支持，他们将提供一个杰出的环境，以促进他的职业发展，以促进他的职业发展。