Mechanisms of invariant NKT cell-mediated in vivo anti-tumor responses

恒定 NKT 细胞介导的体内抗肿瘤反应机制

基本信息

批准号：
8523807
负责人：
Hamid Bassiri
金额：
$ 13.54万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-06 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523807
关键词：
Advisory Committees Antigen-Antibody Complex Antigens Applications Grants Biological Assay Biological Models CD8B1 gene Cells Cellular biology Childhood Clinical Clinical Skills Committee Members Communicable Diseases Complex Confocal Microscopy Cytolysis Development Environment Exhibits Exposure to Faculty Family Fellowship Flow Cytometry Future Gagging Glycolipids Goals Hereditary Malignant Neoplasm Human Hybridomas Image Immunity Immunocompetent Immunocompromised Host Immunologic Monitoring Immunotherapy In Vitro Interferons Interleukin-2 International Jordan Kinetics Lead Leukocytes Luciferases Lymphocyte Lymphocyte Biology Lytic Mediating Medicine Mentors Messenger RNA Mus Oranges Pediatric Hospitals Pediatrics Pennsylvania Philadelphia Physicians Play Postdoctoral Fellow Process Production Program Development Proteins Receptor Signaling Regimen Research Research Institute Residencies Resources Rest Role Scientist Signal Transduction Students Synapses System T-Cell Activation T-Cell Receptor T-Lymphocyte TNF-related apoptosis-inducing ligand Testing Training Training Programs Tumor Burden Tumor Necrosis Factor Ligand Superfamily Member 6 Universities anticancer research authority base cancer therapy career cell killing cytokine cytotoxic cytotoxicity experience granzyme B in vivo in vivo Model insight killer T cell killings member neoplastic cell novel pathogen perforin professor programs reconstitution response skills tumor tumor growth tumor immunology vaccinology

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a 4-year training program for the development of my academic career in Pediatric Infectious Diseases. I have completed formal residency in General Pediatrics and subspecialty fellowship training in Pediatric Infectious Diseases at the Children's Hospital of Philadelphia (CHOP), and am now expanding my scientific skills in NKT cell biology and tumor immunology, and developing my clinical skills in the infectious diseases of immunocompetent and immunocompromised hosts. Drs. Kim Nichols and Gary Koretzky will be mentoring my scientific development. Dr. Nichols, the Director of the Hereditary Cancer Disposition Program at CHOP, and Associate Professor of Pediatrics at the University of Pennsylvania (Penn), is an expert in NKT cell biology. Dr. Nichols has a growing track record of developing the careers of fellows, post-doctoral trainees, and junior faculty. To make my mentoring team as strong as possible, Dr. Nichols has partnered with Dr. Koretzky, Vice-Chair of Research and Chief Scientific Officer in the Department of Medicine at Penn, and the Director of the Signal Transduction Program in the Abramson Family Cancer Research Institute. Dr. Koretzky is an international authority on lymphocyte biology and T cell signal transduction with extensive experience in successfully mentoring numerous students, post-doctoral fellows, and junior faculty members. To further promote my scientific development, I have composed a Scientific Advisory Committee of highly-regarded physician-scientists consisting of Drs. Jordan Orange, Stephan Grupp, and Jeffrey Bergelson. Additionally, Dr. Paul Offit, Maurice Hilleman Endowed Chair in Vaccinology, Professor of Pediatrics at Penn, and Chair of Infectious Diseases at CHOP, will help guide me regarding my clinical development. The proposed research focuses on the tumor immunosurveillance mediated by invariant natural killer T (iNKT) cells. iNKT cells are innate lymphocytes that play critical roles in host immunity, including protection from specific pathogens and tumors. These cells are known to participate in anti-tumor responses indirectly via the robust production of cytokines that promote the anti-tumor activity of natural killer (NK) and CD8+ T cells. In studies using the iNKT cell hybridoma line, DN3A4-1.2, and primary murine and human iNKT cells, I find that iNKT cells themselves exhibit direct cytotoxicity in vitro against CD1d-positive tumors when the target cells are loaded with stimulatory glycolipid antigens. Additionally, in the absence of perforin, this in vitro iNKT cytotoxicity is greatly reduced. Finally, in an in vivo model in which the direct tumor surveillanc capacity of iNKT cells can be evaluated in the absence of other lymphocytes, I find that murine iNKT cells are sufficient for clearance of CD1d-expressing glycolipid-loaded tumors. Based on these observations, I propose to further dissect the mechanisms governing iNKT cell-mediated immunosurveillance. Specifically, I will define the optimal requirements for control of tumor growth in vivo by murine and human iNKT cells and the importance of stimulatory glycolipid antigens in this process (AIM 1). In AIM 2, I will examine the expression and cellular localization of cytolytic effector molecules in resting and activated murine and human iNKT cells, and then evaluate the requirement of these molecules for in vivo tumor immunosurveillance. Finally, in AIM 3, I will examine whether the stimulatory cytokine interleukin-2 augments iNKT cell cytotoxicity in vitro and in vivo and I will explore the mechanisms underlying the augmentation of iNKT cell killing capacity. The completion of the proposed studies will help define the direct axis of iNKT cell cytotoxicity and tumor immunosurveillance in vivo, and should provide insights into the future use of these cells in the adoptive cellular therapy of cancer. Collectively, CHOP and Penn provide an ideal scientific environment for my training as a physician-scientist. I will take advantage of the intellectual strength and academic track-record of my co- mentors and scientific advisory committee members, and the robust availability of expertise, facilities, and resources afforded at CHOP and Penn to accomplish this proposed training program.

描述（由申请人提供）：该提案描述了一项为期4年的培训计划，以开发我在儿科传染病方面的学术生涯。我已经在费城儿童医院（CHOP）完成了一般儿科和小儿传染病培训的正式居住培训，现在正在扩大我在NKT细胞生物学和肿瘤免疫学方面的科学技能，并在感染性疾病中发展了我的临床疾病，这些疾病是由免疫疾病的感染性疾病的临床疾病。博士。金·尼科尔斯（Kim Nichols）和加里·科雷茨基（Gary Koretzky）将指导我的科学发展。宾夕法尼亚大学（Penn）（宾夕法尼亚大学）的遗传性癌症处理计划主任尼科尔斯（Nichols）博士是NKT细胞生物学的专家。尼科尔斯博士在发展研究员，博士后学员和初级教职员工的职业生涯方面有着越来越多的记录。为了使我的指导团队尽可能强大，尼科尔斯博士与宾夕法尼亚州研究副主席兼首席科学官科雷茨基博士以及艾布拉姆森家庭癌症研究所的信号转导计划主任。 Koretzky博士是国际淋巴细胞生物学和T细胞信号转导权，并在成功指导众多学生，博士后研究员和初级教职员工方面具有丰富的经验。为了进一步促进我的科学发展，我成立了一个由DRS组成的高级医师 - 科学家的科学咨询委员会。乔丹·奥兰治（Jordan Orange），斯蒂芬·格鲁普（Stephan Grupp）和杰弗里·伯格森（Jeffrey Bergelson）。此外，莫里斯·希尔曼（Maurice Hilleman）保罗·奥菲特（Paul Offit）博士授予了疫苗科学主席，宾夕法尼亚州的儿科教授和CHOP的传染病主席，将有助于指导我有关我的临床发展。拟议的研究重点是由自然杀伤剂（Inkt）细胞介导的肿瘤免疫监测。 Inkt细胞是先天淋巴细胞，在宿主免疫中起关键作用，包括保护特定病原体和肿瘤。已知这些细胞通过促进天然杀伤（NK）和CD8+ T细胞的抗肿瘤活性的细胞因子的强大产生而间接参与抗肿瘤反应。在使用Inkt细胞杂交瘤系，DN3A4-1.2以及原代鼠和人Inkt细胞的研究中，我发现Inkt细胞本身在体外对CD1D阳性肿瘤表现出直接的细胞毒性，当时靶细胞用刺激性糖脂抗原抗原加载。此外，在没有穿孔蛋白的情况下，这种体外INKT细胞毒性大大降低。最后，在一个体内模型中，在没有其他淋巴细胞的情况下可以评估iNKT细胞的直接肿瘤监测能力，我发现鼠INKT细胞足以清除表达CD1D的糖脂加载肿瘤。基于这些观察结果，我建议进一步剖析有关INKT细胞介导的免疫监视的机制。具体而言，我将定义鼠和人inkt细胞在体内控制肿瘤生长的最佳要求，以及在此过程中刺激性糖脂抗原的重要性（AIM 1）。在AIM 2中，我将检查表达和细胞定位在静止和活化的鼠和人inkt细胞中的细胞溶解效应分子的分子，然后评估这些分子对体内肿瘤免疫监视的需求。最后，在AIM 3中，我将检查刺激性细胞因子白细胞介素2是否会在体外和体内增强Inkt细胞细胞毒性，并将探索Inkt细胞杀死能力增强的机制。拟议研究的完成将有助于定义直接轴在体内inkt细胞细胞毒性和肿瘤免疫监测，应提供对这些细胞在癌症的过继细胞治疗中的未来使用的见解。 Chop和Penn总的来说，为我作为医师科学家的培训提供了理想的科学环境。我将利用我的合作社和科学咨询委员会成员的智力实力和学术轨道记录，以及在Chop和Penn提供的专业知识，设施和资源的强大可用性，以完成这项拟议的培训计划。