DNASE1L3 regulation of anti-tumor immune responses following radiation therapy

项目摘要 这一建议的关键初步数据与树突状细胞有关，树突状细胞是一种连接天然免疫细胞的关键免疫细胞。 检测对适应性免疫反应的感染，可以唯一地针对和摧毁目标。这些是相同的 原理适用于启动和控制对癌症的免疫反应。我们发现，在那些 树突状细胞无法产生适应性免疫来协助放射治疗后的肿瘤治愈 成熟。这些未能成熟的树突状细胞表达一种名为Dnase113的新靶基因，该基因已被 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 该基因在抗肿瘤免疫中的作用及其机制的创新性研究 在肿瘤中的树突状细胞中被调节。 我们假设DNAse113在肿瘤环境中抑制先天和获得性免疫反应。 本研究的具体目的是：1.确定Dnase1l3的髓系表达对急性髓系白血病的影响 放射治疗的免疫反应；2：对髓系细胞表达的影响的无偏分析 DNase113对放射治疗后肿瘤免疫环境的影响。我们的研究设计结合了CT- 多个真实胰腺肿瘤模型的引导放射治疗并使用一系列的RT剂量和 分馏。这些与独特的基因敲除和分析相结合，使我们能够识别分歧 体外和体内的反应。我们对临床样本的分析使用了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对天然佐剂的生物反应的影响 样本。

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.