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: 8279030
• 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/8279030
• 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）：本提案描述了一个为期4年的培训计划，为我的学术生涯在儿科传染病的发展。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感染性疾病的专科奖学金培训，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，并发展我在免疫功能正常和免疫功能低下宿主感染性疾病方面的临床技能。金·尼科尔斯博士和加里·科瑞茨基博士将指导我的科学发展。Nichols博士是CHOP遗传性癌症处置计划的主任，宾夕法尼亚大学（Penn）儿科副教授，是NKT细胞生物学专家。Nichols在发展研究员，博士后学员和初级教师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，Nichols博士与宾夕法尼亚大学医学系研究副主席兼首席科学官Koretzky博士以及Abramson家庭癌症研究所信号转导项目主任合作。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，我组建了一个由高度重视的医学科学家组成的科学咨询委员会，由Jordan橙子博士、Stephan Grupp博士和Jeffrey Bergelson博士组成。此外，Maurice Hilleman疫苗学教授、宾夕法尼亚大学儿科教授和CHOP传染病主席Paul Offit博士将帮助指导我的临床发展。拟开展的研究主要集中在由不变的自然杀伤T（iNKT）细胞介导的肿瘤免疫监视。iNKT细胞是在宿主免疫中起关键作用的先天性淋巴细胞， 包括对特定病原体和肿瘤的保护。已知这些细胞通过促进自然杀伤（NK）和CD 8 + T细胞的抗肿瘤活性的细胞因子的稳健产生间接参与抗肿瘤应答。在使用iNKT细胞杂交瘤系DN 3A 4 -1.2以及原代鼠和人iNKT细胞的研究中，我发现当靶细胞装载刺激性糖脂抗原时，iNKT细胞本身在体外对CD 1d阳性肿瘤表现出直接的细胞毒性。此外，在不存在穿孔素的情况下，这种体外iNKT细胞毒性大大降低。最后，在一个体内模型中，iNKT细胞的直接肿瘤监视能力可以在没有其他淋巴细胞的情况下进行评估，我发现鼠iNKT细胞足以清除表达CD 1d的糖脂负载肿瘤。基于这些观察，我建议进一步剖析iNKT细胞介导的免疫监视机制。具体来说，我将定义的最佳要求，在体内控制肿瘤生长的小鼠和人的iNKT细胞和刺激糖脂抗原在这一过程中的重要性（AIM 1）。在AIM 2中，我将检查表达和细胞定位， 在静息和活化的鼠和人iNKT细胞中的溶细胞效应分子，然后评估这些分子用于体内肿瘤免疫监视的需求。最后，在AIM 3中，我将研究刺激性细胞因子白细胞介素-2是否在体外和体内增强iNKT细胞的细胞毒性，并探讨增强iNKT细胞杀伤能力的机制。完成拟议的研究将有助于确定直轴 iNKT细胞的细胞毒性和体内肿瘤免疫监视，并应提供这些细胞在癌症的过继细胞治疗中的未来用途的见解。总的来说，CHOP和宾夕法尼亚大学为我作为一名医生科学家的培训提供了一个理想的科学环境。我将利用我的合作导师和科学咨询委员会成员的智力力量和学术记录，以及CHOP和Penn提供的专业知识，设施和资源的强大可用性来完成这项拟议的培训计划。