T cells in neurofibroma pathogenesis and malignanttransformation

点击翻译按钮获取中文摘要

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.