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

• 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
• 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

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）：此提案描述了我在儿科传染病学术生涯发展的四年培训计划。我已经在费城儿童医院（CHOP）完成了普通儿科的正式住院医师和儿科传染病的亚专科奖学金培训，现在正在扩展我在NKT细胞生物学和肿瘤免疫学方面的科学技能，并在免疫功能正常和免疫功能低下宿主的传染病方面发展我的临床技能。Drs。金·尼科尔斯和加里·科瑞茨基将指导我的科学发展。Nichols博士是CHOP遗传癌症处置项目主任，宾夕法尼亚大学儿科学副教授，是NKT细胞生物学方面的专家。Nichols博士在发展研究员、博士后实习生和初级教员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大学医学部研究副主席兼首席科学官、艾布拉姆森家族癌症研究所信号转导项目主任科雷茨基博士合作。Koretzky博士是淋巴细胞生物学和T细胞信号转导方面的国际权威，在成功指导众多学生，博士后研究员和初级教师方面拥有丰富的经验。为了进一步促进我的科学发展，我成立了一个由备受尊敬的内科科学家组成的科学咨询委员会。Jordan Orange， Stephan Grupp和Jeffrey Bergelson。此外，Paul Offit博士，Maurice Hilleman疫苗学教授，宾夕法尼亚大学儿科学教授，CHOP感染性疾病主席，将帮助指导我的临床发展。本研究主要针对不变性自然杀伤T （iNKT）细胞介导的肿瘤免疫监视进行研究。iNKT细胞是先天淋巴细胞，在宿主免疫中起关键作用，