T cells in neurofibroma pathogenesis and malignanttransformation

T细胞在神经纤维瘤发病机制和恶性转化中的作用

• 批准号: 10506933
• 负责人: STEVEN DAVID RHODES
• 金额: $ 18.43万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10506933
• 关键词: Address; Advanced Malignant Neoplasm; Affect; Automobile Driving; Benign; CDKN2A gene; CTLA4 gene; Cause of Death; Cell Communication; Cell Shape; Cells; Cellular biology; Cessation of life; Chemoprevention; Clone Cells; Development; Disease; Doctor of Philosophy; Ecosystem; Embryo; Environment; Evaluation; Event; Evolution; Excision; Exhibits; Five-Year Plans; Funding; Genetic Predisposition to Disease; Genetically Engineered Mouse; Heritability; Heterogeneity; Human; Immune; Immunocompetent; Immunologic Surveillance; Immunologics; Immunooncology; Immunophenotyping; Incidence; Indiana; Individual; Knowledge; Laboratories; Laboratory Research; Malignant - descriptor; Malignant Neoplasms; Mediating; Medical; Mentors; Molecular; NF1 gene; Neoplastic Schwann Cell; Neurofibromatoses; Neurofibromatosis 1; Neurofibrosarcoma; Oncogenic; Oncology; Pathogenesis; Patients; Pediatric Hematology; Pediatric Research; Pediatrics; Peripheral Nerve Sheath Neoplasm; Peripheral Nervous System Neoplasms; Persons; Phenotype; Physicians; Play; Plexiform Neurofibroma; Prognosis; Research; Research Personnel; Residencies; Resolution; Resources; Risk; Role; Sampling; Schwann Cells; Scientist; Shapes; Suspensions; Syndrome; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Training; Training Programs; Tumor Immunity; Tumor Suppressor Proteins; Tumor stage; Tumor-infiltrating immune cells; United States National Institutes of Health; Universities; Validation; Work; antagonist; base; cancer predisposition; care burden; career; checkpoint inhibition; density; deprivation; disease natural history; effective therapy; exhaust; exhaustion; hyperactive Ras; improved; insight; macrophage; mast cell; medical schools; mouse model; mutant; neurofibroma; neutralizing antibody; new therapeutic target; novel; novel strategies; pathogen; pediatric department; pre-clinical; precursor cell; premalignant; premature; prevent; programs; receptor; response; sarcoma; stemness; treatment strategy; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis; tumorigenic

PROJECT SUMMARY This proposal describes a five-year plan to prepare Steven Rhodes MD, PhD for independence as a physician scientist studying the immuno-oncologic interfaces of neurofibromatosis (NF1)-associated peripheral nerve sheath tumor progression. Dr. Rhodes completed his MD, PhD training at the Indiana University Medical Scientist Training Program. Upon completion of his Pediatrics residency, he matriculated to subspecialty training in Pediatric Hematology-Oncology, where he joined the laboratory of Dr. Wade Clapp and generated novel genetically engineered mouse models (GEMMs) recapitulating the progression of benign plexiform and precancerous atypical neurofibromas to malignant peripheral nerve sheath tumor (MPNST), a devastating form of sarcoma that is the leading cause of death in persons with NF1. These GEMMs provide a tractable platform to study the role of the immune microenvironment in governing the evolution of tumors along the neurofibroma to MPNST continuum. Leveraging these GEMMs and samples from human NF1 patients, Dr. Rhodes discovered that precancerous atypical neurofibromas are heavily infiltrated by T cells and exhibit signatures of enhanced immune surveillance. These findings led us to hypothesize that T cells play a key role in preventing the outgrowth of malignant clones in these precancerous tumors. The aims of this research are to 1) Define at single cell resolution the clonal heterogeneity and functional states of infiltrating T cells in mouse models that recapitulate the malignant transformation of plexiform and atypical neurofibroma; 2) Dissect spatial interaction networks between infiltrating T cells and neoplastic Schwann cells within native tumor samples from NF1 patients; and 3) Establish the utility of immune checkpoint inhibition, via CTLA-4 antagonism, to forestall malignant transformation by potentiating T cell mediated anti-tumor activity in pre-cancerous atypical neurofibroma. Indiana University School of Medicine and the Herman B Wells Center for Pediatric Research provides an exceptional training environment for Dr. Rhodes to develop his research laboratory. The Department of Pediatrics has an exceptional track record of NIH funded research (currently 6th in the nation) and offers access to all the necessary resources for Dr. Rhodes to carry out the proposed scope of work. Dr. Clapp (primary research mentor) is the co-PI of an NCI funded Developmental and Hyperactive Ras Tumor SPORE, focused on NF1-associtated tumors, and has an exceptional track record of training young physician scientists. Dr. Rhodes has assembled a diverse panel of mentors that will allow him to develop new expertise in T cell biology, immuno-oncology and single cell analytics that will serve to distinguish him from his primary mentor and other investigators in his field. Importantly, uncovering the cellular and molecular mechanisms modulating the progression of NF1-associated peripheral nerve sheath tumors will provide key insight into the pathobiology of the disease and identify novel therapeutic targets for treatment or ultimately chemoprevention, for which no effective therapies exist currently.

项目概要 该提案描述了一个五年计划，旨在帮助史蒂文·罗兹 (Steven Rhodes) 医学博士、博士做好独立成为一名医生的准备 科学家研究神经纤维瘤病（NF1）相关周围神经的免疫肿瘤学界面 鞘膜肿瘤进展。 Rhodes 博士在印第安纳大学医学院完成了医学博士、博士培训 科学家培训计划。完成儿科住院医师培训后，他进入了亚专业培训 在儿科血液学-肿瘤学领域，他加入了 Wade Clapp 博士的实验室，并产生了新颖的 基因工程小鼠模型（GEMM）概括了良性丛状和 癌前非典型神经纤维瘤到恶性周围神经鞘瘤（MPNST），这是一种破坏性的形式 肉瘤是 NF1 患者死亡的主要原因。这些 GEMM 提供了一个易于处理的平台 研究免疫微环境在控制神经纤维瘤肿瘤进化中的作用 到 MPNST 连续体。 Rhodes 博士利用这些 GEMM 和人类 NF1 患者的样本发现 癌前非典型神经纤维瘤被 T 细胞大量浸润，并表现出增强的特征 免疫监视。这些发现使我们推测 T 细胞在防止肿瘤生长方面发挥着关键作用 这些癌前肿瘤中的恶性克隆。本研究的目的是 1) 定义单细胞 解析小鼠模型中浸润性 T 细胞的克隆异质性和功能状态 丛状和非典型神经纤维瘤的恶变； 2）剖析空间交互网络 NF1 患者天然肿瘤样本中的浸润性 T 细胞和肿瘤性雪旺细胞之间的关系；和 3) 通过 CTLA-4 拮抗作用建立免疫检查点抑制的效用，以预防恶性转化 通过增强 T 细胞介导的癌前非典型神经纤维瘤的抗肿瘤活性。 印第安纳大学医学院和赫尔曼·B·威尔斯儿科研究中心提供了 为罗兹博士发展他的研究实验室提供了特殊的培训环境。该部门 儿科在 NIH 资助的研究方面拥有卓越的记录（目前在全国排名第六），并提供访问机会 为罗德博士开展拟议的工作范围提供所有必要的资源。克拉普博士（小学 研究导师）是 NCI 资助的发育和过度活跃 Ras 肿瘤 SPORE 的联合 PI，专注于 研究人员对 NF1 相关肿瘤进行了研究，并在培训年轻医师科学家方面拥有出色的记录。博士。 Rhodes 组建了一个多元化的导师小组，这将使他能够在 T 细胞生物学领域发展新的专业知识， 免疫肿瘤学和单细胞分析将使他与他的主要导师和其他人区分开来 其领域的研究人员。重要的是，揭示调节的细胞和分子机制 NF1相关外周神经鞘肿瘤的进展将为了解该肿瘤的病理学提供重要见解 疾病并确定新的治疗靶点进行治疗或最终进行化学预防，对此没有 目前存在有效的治疗方法。