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

• 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
• 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

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 这项提议的关键初步数据与树突细胞有关，树突细胞是一种关键的免疫细胞， 感染检测到适应性免疫反应，可以独特的目标和破坏目标。这些相同 这些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， 放射治疗后，由于无法产生适应性免疫来帮助肿瘤治愈，树突状细胞无法产生适应性免疫， 成熟这些未能成熟的树突状细胞表达一种名为Dnase 1 l3的新靶基因， 显示出负调节先天刺激和负调节自身免疫反应。这项建议是 对该基因在抗肿瘤免疫中的作用及其作用机制的创新研究。 在肿瘤中的树突状细胞中调节。 我们假设DNAse 1 l3抑制肿瘤环境中的先天性和适应性免疫反应。 本研究的具体目的是：1.确定Dnase 113髓样表达的结果， 对放射治疗的免疫应答; 2：骨髓表达的结果的无偏倚分析 dnase 1 l3对放射治疗后肿瘤免疫环境的影响。我们的研究设计包括CT- 多个真实胰腺肿瘤模型的引导放射治疗，并使用一系列RT剂量， 分馏。这些与独特的敲除和检测相结合，使我们能够识别不同的 在体外和体内的反应。我们对临床样本的分析使用高质量的生物信息学方法， 使我们能够评估肿瘤环境对患者先天性佐剂生物学应答的影响， 样品