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Elucidate and Modulate Cell Signaling in NK Cells for Glioma Treatment

阐明和调节 NK 细胞中的细胞信号传导用于神经胶质瘤治疗

基本信息

批准号：
9240181
负责人：
Jianhua Yu
金额：
$ 38.75万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-18 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240181
关键词：
Alpha Cell Animal Model Authorship Award Blood Blood - brain barrier anatomy Bone Morphogenetic Proteins Brain Neoplasms Budgets Cell Maturation Cell Therapy Cell physiology Cells Central Nervous System Infections Clinical Trials Cytotoxic T-Lymphocytes Data Development Diagnosis Effector Cell Engineering FDA approved FOXO1A gene Family Foundations Future Genes Glioblastoma Glioma Granzyme Herpesvirus 1 Homeostasis Hour Human Immune Immunity Immunosuppression In Vitro Investigation Juvenile polyposis syndrome Laboratories Legal patent Lymph Malignant Neoplasms Malignant neoplasm of brain Manuscripts Mediating Modeling Molecular Mus Natural Immunity Natural Killer Cells Neoplasm Metastasis Oncolytic Oncolytic viruses Operative Surgical Procedures Pathway interactions Patients Peer Review Pre-Clinical Model Progress Reports Protein Inhibition Publications Published Comment Publishing Radiation therapy Reporting Research Research Personnel Role Sampling Signal Pathway Signal Transduction Signaling Protein Smad Proteins Testing Time Transforming Growth Factor alpha Transforming Growth Factor beta Treatment Efficacy United States National Institutes of Health Up-Regulation Viral Virotherapy Wild Type Mouse Work base cancer therapy cell killing chemotherapy chimeric antigen receptor cytotoxic cytotoxicity design editorial forkhead protein gene repression improved improved outcome in vivo inhibitor/antagonist insight killings leukemia loss of function mutation mouse model neoplastic cell novel novel therapeutics oncolytic virotherapy receptor response success trafficking trend tumor tumor growth

项目摘要

Project Summary Natural killer (NK) cells are a critical component of innate immunity and are cytolytic to tumor cells and viral- infected cells. Oncolytic herpes simplex virus 1 (oHSV), which has recently been approved by the FDA for the treatment of cancer, holds great potential in the treatment of glioblastoma (GBM), a highly lethal brain tumor. However, based on our previous studies, host NK cells provide a rapid and robust response following central nervous system (CNS) infection with oHSV, thus presenting a barrier for effective oncolytic virotherapy for GBM. Cytotoxic genes, including granzyme B (Gzmb), determine NK cell cytolytic activity in these settings; however, the molecular mechanisms responsible for regulating Gzmb expression are largely unknown. In this application, our preliminary data show that Smad4, a co-Smad protein in the TGF-beta superfamily signaling pathway, positively regulates Gzmb expression in a TGF-beta-independent manner, which correlates with decreased anti-tumor activity in mice with an NK-specific Smad4 deficiency. Using this mouse model, we also discovered that Smad4 positively regulates NK cell homeostasis and maturation by upregulating Blimp1, a positive regulator of NK cell maturation. Smad4 is also a co-Smad in bone morphogenetic protein (BMP) signaling. Our preliminary data support the hypothesis that the TGF-β-independent role of Smad4 in regulating NK cell function is downstream of BMP signaling, which has been reported to positively regulate NK cell function. Here, we propose to explore the mechanisms for this conceptually novel discovery and to modulate BMP-Smad4 signaling in NK cells in the setting of oncolytic virotherapy for GBM. Our overall hypothesis is that Smad4 positively regulates NK cell development and cytotoxicity against target cells including oHSV-infected GBM cells, and this can be modulated by temporarily inhibiting BMP-Smad4 signaling to enhance the efficacy of oHSV therapy. We propose an in-depth investigation into the molecular mechanisms whereby smad4 positively regulates Gzmb expression, cytotoxicity, and development of NK cells in mice using our aforementioned animal model and in humans using samples of patients with familial juvenile polyposis (FJP), having a germline loss-of-function mutation in Smad4. Additionally, we also propose to modulate BMP- Smad4 signaling to temporarily inhibit NK cell responses to oHSV to enhance its efficacy for the treatment of GBM. These are outlined in three Aims to test our hypothesis. Aim 1 is to dissect the mechanisms by which Smad4 positively regulates NK cell cytotoxicity against target cells. Aim 2 is to characterize the mechanisms by which Smad4 positively regulates NK cell development. Aim 3 is to temporarily inhibit BMP-Smad4 signaling in NK cells to improve oncolytic viral therapy for GBM in vitro and in vivo. We believe that the results of these studies will lend new insights into basic mechanisms of cytotoxic cell therapy and that exploration of novel therapeutics in preclinical models will advance the treatment of GBM.

项目总结