DNASE1L3 regulation of anti-tumor immune responses following radiation therapy

DNASE1L3 对放射治疗后抗肿瘤免疫反应的调节

基本信息

批准号：
10577698
负责人：
Michael James Gough
金额：
$ 23.42万
依托单位：
PROVIDENCE HEALTH & SERVICES - OREGON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10577698
关键词：
Adjuvant Affect Autoimmune Autoimmune Responses Bioinformatics Biological Biological Assay Biology Cancer Patient Cells Clinical Data Dendritic Cells Deoxyribonucleases Detection Development Dose Encapsulated Environment Enzymes Fractionation Future Genes Goals Immune Immune response Immunobiology In Vitro Infection Innate Immune Response Investigation Knock-out Link Macrophage Malignant Neoplasms Measures Modeling Molecular Mus Myelogenous Myeloid Cells Nucleic Acids Outcome Patients Polynucleosome Pre-Clinical Model Radiation therapy Reagent Regimen Regulation Repression Research Design Risk Role Sampling Series Signal Transduction Stimulus T cell response Testing Tumor Immunity adaptive immune response adaptive immunity anti-tumor immune response cancer cell cancer immunotherapy cancer therapy combinatorial conditional knockout drug development high reward immunogenic improved in vivo innovation microvesicles new therapeutic target novel pancreatic cancer model radiation response response therapeutic target treatment effect tumor

项目摘要

Project Summary The critical preliminary data for this proposal relates to dendritic cells, a critical immune cell that links innate detection of infection to adaptive immune responses that can uniquely target and destroy targets. These same principles apply to initiate and control immune responses to cancer. We discovered that in tumors that are unable to generate adaptive immunity to assist in tumor cure following radiation therapy, dendritic cells fail to mature. These dendritic cells that fail to mature express a novel target gene called Dnase1l3, which has been shown to negatively regulate innate stimuli, and to negatively regulate autoimmune responses. This proposal is an innovative investigation into the role of this gene in anti-tumor immunity, and the mechanisms by which it is regulated in dendritic cells in tumors. We hypothesize that DNAse1l3 represses innate and adaptive immune responses in the tumor environment. The specific aims of this study are to 1: Determine the consequence of myeloid expression of Dnase1l3 on the immune response to radiation therapy; 2: Unbiased analysis of the consequence of myeloid expression of Dnase1l3 on the tumor immune environment following radiation therapy. Our study design incorporates CT- guided radiation therapy of multiple authentic pancreatic tumor models and using a range of RT doses and fractionations. These are combined with unique knockouts and assays that allow us to identify divergent responses in vitro and in vivo. Our analyses of clinical samples use high quality bioinformatic approaches that allow us to evaluate effect of the tumor environment on the biological response to innate adjuvants in patient samples.

项目摘要该提案的关键初步数据与树突状细胞有关，这是一种关键的免疫细胞，与先天性联系起来检测感染以唯一靶向和破坏靶标的适应性免疫反应。这些一样原则适用于启动和控制对癌症的免疫反应。我们发现在肿瘤中在放射治疗后无法产生适应性免疫以协助肿瘤治疗，树突状细胞无法成熟。这些未能成熟的树突状细胞表达了一个新的靶基因，称为dnase1l3，它一直是表现为负调节先天刺激，并对自身免疫反应进行负调节。该提议是对该基因在抗肿瘤免疫中的作用的创新研究以及它的机制在肿瘤中的树突状细胞中调节。我们假设DNase1L3在肿瘤环境中抑制先天和适应性免疫反应。这项研究的具体目的是1：确定dnase1l3在对放射治疗的免疫反应； 2：对髓样表达的后果的无偏分析放射治疗后肿瘤免疫环境上的DNase1L3。我们的研究设计包含CT- 多种正宗胰腺肿瘤模型的引导放射疗法，并使用一系列RT剂量和分馏。这些结合了独特的淘汰和测定，使我们能够识别出分歧体外和体内反应。我们对临床样本的分析使用高质量的生物信息学方法允许我们评估肿瘤环境对患者先天佐剂的生物反应的影响样品。