T cells in neurofibroma pathogenesis and malignanttransformation

项目总结 这份提案描述了一项五年计划，为史蒂文·罗兹医学博士独立成为一名内科医生做准备 研究神经纤维瘤病(NF1)相关周围神经的免疫肿瘤学界面的科学家 鞘状瘤进展。罗兹博士在印第安纳大学医学院完成了他的医学博士培训 科学家培训计划。完成儿科住院医师训练后，他进入专科训练。 在儿科血液学-肿瘤学，他加入了韦德·克拉普博士的实验室，并创作了一本小说 基因工程小鼠模型(GEMM)概括了良性丛状和 癌前不典型神经纤维瘤到恶性周围神经鞘瘤(MPNST)，一种破坏性的形式 肉瘤是NF1患者的主要死亡原因。这些GEMM提供了一个易于处理的平台 免疫微环境在神经纤维瘤肿瘤演变中的作用研究 到MPNST连续体。利用这些GEMM和来自人类NF1患者的样本，罗兹博士发现 癌前非典型神经纤维瘤被T细胞大量渗透并表现出强化的征象 免疫监视。这些发现使我们假设T细胞在防止肿瘤生长中起着关键作用 这些癌前肿瘤中的恶性克隆。这项研究的目的是：1)定义单细胞 重述小鼠模型中浸润性T细胞的克隆异质性和功能状态的解析 丛状和不典型神经纤维瘤的恶变；2)空间相互作用网络的解剖 NF1患者自然肿瘤标本中浸润性T细胞和肿瘤雪旺细胞之间的关系；3) 通过CTLA-4拮抗确定免疫检查点抑制在预防恶性转化中的作用 在癌前非典型神经纤维瘤中通过增强T细胞介导的抗肿瘤活性。 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。美国商务部 儿科在NIH资助的研究方面有着出色的记录(目前在全国排名第六)，并提供 为罗兹博士执行拟议的工作范围提供所有必要的资源。克拉普博士(初级 研究导师)是NCI资助的发育和高度活跃的RAS肿瘤孢子的联合PI，专注于 对NF1相关肿瘤的研究，并在培训年轻内科科学家方面有着出色的记录。Dr。 罗兹已经组建了一个多样化的导师小组，这将使他能够在T细胞生物学方面开发新的专业知识。 免疫肿瘤学和单细胞分析将有助于将他与他的主要导师和其他 他所在领域的调查人员。重要的是，揭示了细胞和分子机制调节 NF1相关周围神经鞘膜瘤的研究进展将为深入了解NF1相关周围神经鞘瘤的病理生物学机制提供重要信息。 并找出治疗或最终化学预防的新的治疗靶点，对此没有 目前存在有效的治疗方法。

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.