Contribution of myeloid cells to the anti-tumor adaptive immune response after radiation in a pediatric brain tumor

骨髓细胞对小儿脑肿瘤放疗后抗肿瘤适应性免疫反应的贡献

• 批准号: 10664681
• 负责人: MAI T DANG
• 金额: $ 23.81万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664681
• 关键词: Ablation; Adult; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Biological Assay; Brain; Brain Glioblastoma; Brain Neoplasms; CD8-Positive T-Lymphocytes; Cause of Death; Cell Survival; Cell physiology; Cells; Cellular Immunity; Child; Childhood; Childhood Brain Neoplasm; Childhood Malignant Brain Tumor; Clinical; Coupled; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Disease remission; Fellowship; Functional disorder; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Head; Heterogeneity; Immune; Immune response; Immune system; Immunity; Immunology; Immunosuppression; Immunotherapy; Impairment; Infiltration; Institution; Intervention; Investigation; Knowledge; Laboratories; Macrophage; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Mediating; Mentors; Mentorship; Microglia; Morbidity - disease rate; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Natural Immunity; Neurology; Neurosciences; Neutrophil Infiltration; Non-Small-Cell Lung Carcinoma; Oncology; Operative Surgical Procedures; Patients; Pediatric Hospitals; Pediatric Neurology; Pharmaceutical Preparations; Phenotype; Philadelphia; Physicians; Play; Population; Positioning Attribute; Radiation; Radiation therapy; Recurrence; Regulation; Research; Resistance; Role; Scientist; Seasons; Site; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic Intervention; Training; Training Programs; Treatment Efficacy; Tumor Immunity; Universities; Washington; Work; adaptive immune response; adaptive immunity; anti-tumor immune response; antitumor effect; arm; cancer stem cell; career; cell killing; chemotherapy; clinical training; cytotoxic; draining lymph node; immune checkpoint blockade; improved; improved outcome; medulloblastoma; melanoma; monocyte; neoplastic cell; nervous system disorder; neuro-oncology; neutrophil; new therapeutic target; novel; novel therapeutics; pediatric patients; professor; radiation effect; recruit; response; side effect; single cell analysis; skill acquisition; tenure track; tool; transcriptomics; treatment response; treatment strategy; tumor; tumor immunology; tumor microenvironment; tumor-immune system interactions

Project Summary The goal of the proposed 5-year training program is to facilitate Dr. Mai Dang’s full transition to an independent physician scientist. Her work is focused on identifying novel ways to modulate the brain tumor immune microenvironment to improve treatment strategies for pediatric patients. Dr. Dang’s research background is in neuroscience and her clinical training in pediatric neurology, which was completed at the Children’s Hospital of Philadelphia. After clinical fellowship, she received additional clinical training in neuro- oncology while completing her fellowship research on identifying the heterogeneity of myeloid cells in medulloblastoma. She was recently recruited to Washington University in St. Louis as a tenured-track assistant professor in the Department of Neurology to continue this work with strong institutional support. She will use the next five years of mentored training to acquire additional essential knowledge on immunology and advanced research tools to perform investigations in cancer immunology. While her prior work was specifically on macrophages and microglia, her current proposal will focus on antigen presenting cells and their interaction with the adaptive arm of the immune system. Dr. Dang will be mentored by Dr. Milan Chheda, a physician scientist, whose expertise is on developing new therapies that target glioblastoma brain tumor cancer stem cells and the tumor microenvironment. She will be co-mentored by Dr. David DeNardo, who has expertise in immunology and the tumor microenvironment’s regulation of therapy response in pancreatic and lung cancer. They will be joined by a committee comprised of two highly seasoned mentors, both physician scientists with excellent track record for and commitment to training other physician scientists at WUSTL. Dr. Christine Gurnett is Head of Pediatric neurology, who is highly recognized for her work in the genetics of neurological disorders, and Dr. Joshua Rubin, Professor in Oncology is an expert on pediatric and adult brain tumors. This team is deeply committed to providing Dr. Dang with scientific, technical, and career mentorship to assist her in this launch of her independent research career. The research goal of this proposal is to identify reversible causes of immune suppression in medulloblastomas treated with radiation. The central hypothesis is that effective tumor immunity after radiation in a pediatric brain tumor will require both reducing suppressive myeloid cells and increasing functional antigen presenting cells. She will use advanced tools such as inducible depletion of immune cells and single-cell analysis paired with assays to directly measure the function of antigen presenting cells and cytotoxic T cells to study this hypothesis. Findings from this work will uncover ways to effectively use immunotherapy to augment radiation efficacy to improve overall survival and morbidity for pediatric brain tumor patients.

项目概要 拟议的 5 年培训计划的目标是促进 Mai Dang 博士全面过渡到 独立医师科学家。她的工作重点是寻找调节脑肿瘤的新方法 免疫微环境改善儿科患者的治疗策略。党博士的研究 她的背景是神经科学，她在儿科神经病学方面接受了临床培训，该培训是在 费城儿童医院。临床研究结束后，她接受了神经方面的额外临床培训 肿瘤学，同时完成她的奖学金研究，以确定骨髓细胞的异质性 髓母细胞瘤。她最近被圣路易斯华盛顿大学聘为终身助理 神经病学系教授在强有力的机构支持下继续这项工作。她会用 未来五年的指导培训，以获得有关免疫学和免疫学的额外基本知识 用于进行癌症免疫学研究的先进研究工具。虽然她之前的工作具体是 关于巨噬细胞和小胶质细胞，她目前的提案将重点关注抗原呈递细胞及其相互作用 与免疫系统的适应性臂。 Dang 博士将接受医生 Milan Chheda 博士的指导 科学家，其专业知识是开发针对胶质母细胞瘤脑肿瘤癌症干细胞的新疗法 细胞和肿瘤微环境。她将由 David DeNardo 博士共同指导，David DeNardo 博士在以下领域拥有专业知识： 免疫学和肿瘤微环境对胰腺癌和肺癌治疗反应的调节。 他们将加入一个由两位经验丰富的导师组成的委员会，两位导师都是医学科学家 WUSTL 拥有出色的记录并致力于培训其他医学科学家。克里斯汀博士 Gurnett 是儿科神经病学的负责人，她在神经病学遗传学方面的工作受到高度认可 肿瘤学教授 Joshua Rubin 博士是儿童和成人脑肿瘤方面的专家。这 团队致力于为 Dang 博士提供科学、技术和职业指导，以帮助她 她的独立研究生涯就此展开。 该提案的研究目标是确定免疫抑制的可逆原因 用放射治疗的髓母细胞瘤。中心假设是辐射后有效的肿瘤免疫 在儿科脑肿瘤中，需要减少抑制性骨髓细胞并增加功能性抗原 呈现细胞。她将使用先进的工具，例如免疫细胞的诱导耗竭和单细胞 分析与直接测量抗原呈递细胞和细胞毒性 T 细胞功能的测定相结合 研究这个假设。这项工作的结果将揭示有效使用免疫疗法来增强疗效的方法 放射疗效可提高儿科脑肿瘤患者的总体生存率和发病率。