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

项目摘要 拟议的5年培训计划的目标是促进麦当博士全面过渡到一个 独立的医学科学家。她的工作重点是确定调节脑肿瘤的新方法 免疫微环境，以改善儿科患者的治疗策略。邓博士的研究 背景是神经科学和她的临床培训，在儿科神经学，这是在完成 费城儿童医院在临床研究之后，她接受了神经学方面的额外临床培训。 在完成她的奖学金研究的同时，她还完成了一项关于识别骨髓细胞异质性的研究， 髓母细胞瘤她最近被圣路易斯的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 未来五年的辅导培训，以获得更多的免疫学基本知识， 先进的研究工具来进行癌症免疫学的研究。虽然她之前的工作 关于巨噬细胞和小胶质细胞，她目前的建议将集中在抗原呈递细胞及其相互作用 免疫系统的适应性手臂。Dang博士将由医生Milan Chheda博士指导 他的专长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。她将由大卫德纳多博士共同指导，他在 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名经验丰富的导师组成的委员会，这两名导师都是医生科学家， 在WUSTL培训其他医生科学家的良好记录和承诺。克莉丝汀医生 Gurnett是儿科神经病学的负责人，她在神经系统遗传学方面的工作得到了高度认可。 肿瘤学教授约书亚鲁宾博士是儿科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 这是她独立研究生涯的开始 这项提案的研究目标是确定免疫抑制的可逆原因， 放射治疗的髓母细胞瘤。中心假设是放射后有效的肿瘤免疫 在儿科脑肿瘤中，需要减少抑制性髓样细胞和增加功能性抗原 呈递细胞她将使用先进的工具，如免疫细胞的诱导性耗竭和单细胞 分析与直接测量抗原呈递细胞和细胞毒性T细胞的功能的测定配对， 研究这个假设。这项工作的结果将揭示有效利用免疫疗法来增强 提高儿童脑肿瘤患者的总体生存率和发病率的放射疗效。

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.