T cells in neurofibroma pathogenesis and malignanttransformation

项目摘要 该提案描述了一个五年计划，以准备史蒂芬罗兹医学博士，博士独立作为一名医生 研究神经纤维瘤病（NF 1）相关外周神经的免疫肿瘤学界面的科学家 鞘瘤进展。罗兹博士在印第安纳州医科大学完成了医学博士和博士培训 科学家培训计划。在完成儿科住院医师培训后， 在儿科血液肿瘤学，在那里他加入了韦德克拉普博士的实验室，并产生了新的 基因工程小鼠模型（GEMM）重现了良性丛状和 癌前非典型神经纤维瘤到恶性外周神经鞘瘤（MPNST），一种破坏性形式 肉瘤是NF 1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肿瘤沿着神经纤维瘤演变中的作用 到MPNST连续体。利用这些GEMM和人类NF 1患者的样本，罗兹博士发现， 癌前非典型神经纤维瘤被T细胞大量浸润， 免疫监视这些发现使我们假设T细胞在防止过度生长中起着关键作用 癌前病变中的恶性克隆本研究的目的是：1）定义单个细胞 解决小鼠模型中浸润性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恶变; 2）解剖空间相互作用网络 在来自NF 1患者的天然肿瘤样品内的浸润性T细胞和肿瘤性雪旺细胞之间;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 通过增强癌前非典型神经纤维瘤中T细胞介导的抗肿瘤活性。 印第安纳州大学医学院和赫尔曼B威尔斯儿科研究中心提供了一个 为罗兹博士发展他的研究实验室提供了特殊的培训环境。部 儿科在NIH资助的研究方面有着卓越的记录（目前在全国排名第六）， 罗兹博士开展拟定工作范围所需的所有必要资源。Clapp博士（初级 研究导师）是NCI资助的发育和过度活跃的Ras肿瘤孢子的共同PI，专注于 NF 1相关肿瘤的研究，并在培训年轻医生科学家方面有着卓越的记录。博士 罗兹组建了一个多元化的导师小组，这将使他能够在T细胞生物学方面发展新的专业知识， 免疫肿瘤学和单细胞分析，这将有助于将他与他的主要导师和其他人区分开来 他所在领域的调查员。重要的是，揭示调节细胞和分子机制， NF 1相关的周围神经鞘肿瘤的进展将为研究神经鞘瘤的病理生物学提供关键的见解。 该疾病和鉴定用于治疗或最终化学预防的新的治疗靶点， 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.