Dynamics of Immune Response in Irradiated Rectal Cancer

摘要 尽管人们认识到免疫系统在癌症对电离辐射的反应中的作用， 成功地转化到诊所是滞后的。我们建议将研究的罗宾机制调整为 能够深入到辐射(RT)和免疫领域。来自七个国际组织的代表 已经从事RT和免疫研究的学术中心聚集在一起，参加了一项小型的 前瞻性临床试验(应计：美国25名患者，欧洲25名患者)，以协同和加速 发现号。直肠癌术前短程放疗(SCRT)的设置已成为一种理想的治疗方案 对于提出的科学问题。SCRT是一种标准的治疗方法，在此之前和之后都要进行结肠镜检查 分别评估肿瘤基线范围和反应(在放射治疗结束时)：在每次结肠镜检查期间同意 患者可以捐献肿瘤活检以及粪便和血液(PBMC)样本。同样的一套标本 可以在六周后的手术中采集，在那里也可以对淋巴进行研究采样， 在RT场内和场外。这些连续的组织集将使我们能够进行尖端的 “组学”方法研究放射治疗领域中的正常组织和癌组织以及微生物组。PBMC 分析将允许在单细胞水平上关联RT诱导的氧化应激，改变 免疫表型和PBMC生物学。同样，分析内外淋巴结节的能力 辐射场将允许在单细胞水平上精确定位RT对每个免疫亚群的影响。这个 对癌症活检的纵向分析，在放疗前后和手术时收集，将提供关于 RT诱导的“组学”改变。一项正交放射组学研究将分析SCRT前和 手术前(也是直肠癌的标准成像程序)以及CT获得的图像 模拟。遵守数据共享、程序和数据标准化的国际规定 获取和统一上传的数据将是这一努力的关键。先进的生物信息学工具将 通过专用的数据共享和综合分析核心进行应用，能够解开和解释 复杂的生物和成像数据，通过利用NCI FireCloud工作区进行分类。通过融合经验丰富的 临床研究人员、生物科学家和生物信息学家，以解决基本的辐射生物学问题， 此Robin将迅速实现前所未有的发现，这些发现将与Robin网络和 整个科学界。 最后，自成立以来，罗宾揭示了交叉培养和交叉受精的最佳环境 参与赠款准备的科学家和临床医生，并为 提出了交叉培训核心，这是一个新的结构，以形成未来的放射肿瘤学和生物学领导者，一项任务 这三位私家侦探都认为对我们纪律的未来至关重要。

ABSTRACT Despite the recognition of the contribution of the immune system to cancer response to ionizing radiation, successful translation to the clinic is lagging. We are proposing to adapt the ROBIN mechanisms of research to enable a deep dive into the field of radiation (RT) and immunity. Representatives from seven international academic centers already engaged in RT and immunity research have converged to participate in a small prospective clinical trial (accrual: 25 patients in US and 25 patients in Europe), to synergize and accelerate discovery. The setting of preoperative short course radiotherapy (SCRT) in rectal cancer, has emerged as ideal for the scientific questions posed. SCRT is a standard treatment, preceded and followed by colonoscopies to respectively assess tumor baseline extent and response (at the end of RT): during each colonoscopy consenting patients can donate a tumor biopsy, as well as stool and blood (PBMC) samples. The same set of specimens can be harvested, six weeks later at surgery, where research sampling of lymph nodes will also be possible, within and outside the RT field. These sequential sets of tissues will enable us to conduct cutting edge multiple “omics” approaches to study irradiated normal and cancer tissue and the microbiome in the RT field. The PBMC analysis will allow correlation at a single cell level between RT-induced oxidative stress, changes in immunophenotype and PBMC biology. Similarly, the ability to analyze lymph nodes harvested inside and outside the radiation field will allow to pinpoint at the single cell level the RT effects on each immune subpopulation. The longitudinal analysis on cancer biopsy, collected before and after RT and at surgery, will give a snapshot on the RT-induced “omics” changes. An orthogonal radiomic study will analyze MR images obtained before SCRT and before surgery (also standard imaging procedures in rectal cancer) together with images obtained at CT simulation. Compliance with international regulations for data sharing, standardization of procedures and data acquisition and harmonization of uploaded data will be essential to this effort. Advanced bioinformatics tools will be applied through a dedicated Data Sharing and Integrative Analysis Core, capable to deconvolute and interpret complex biological and imaging data, sorted by utilizing NCI FireCloud workspaces. By converging experienced clinical investigators, bio-scientists and bio-informaticians to address fundamental radiation biology questions, this ROBIN will rapidly enable unprecedented discovery that will be shared with the ROBIN network and the scientific community at large. Finally, since inception, ROBIN has revealed an optimal environment for cross-training and cross-fertilization of the scientists and clinicians involved in the grant preparation and has created a robust foundation for the proposed Cross Training Core, a novel structure to form future leaders in radiation oncology and biology, a task each of the three P.I.s consider crucial to the future of our discipline.