Washington University (WU) ROBIN Center: MicroEnvironment and Tumor Effects Of Radiotherapy (METEOR)

项目摘要 除了直接杀死快速增殖的肿瘤细胞外，放射治疗(RT)还可以改变肿瘤的免疫功能。RT 增加肿瘤相关抗原的表达和释放，诱导免疫原性细胞死亡，以及 释放危险信号和趋化因子，将免疫细胞招募到肿瘤微环境(TME)。RT 还可以通过增加肿瘤浸润性免疫刺激细胞的数量来增强肿瘤杀伤力 诱导新抗原的表达。然而，RT也刺激其他髓系来源的募集 具有肿瘤允许表型的免疫细胞亚群。这些免疫之间的总体平衡 放射的刺激和抑制效应最终预测局部肿瘤的RT治疗 产生有效和持久的全身性抗肿瘤免疫反应。我们假设RT(和In 特殊的SOC CRT)通过以下方式限制耐药肿瘤的长期抗肿瘤免疫的发展 不成比例地增加骨髓来源细胞(MDCs)的数量和肿瘤允许表型 TME。华盛顿大学放射治疗对肿瘤微环境的影响(流星) 中心将通过与Close进行的动态分子表征试验来验证这一假说 综合研究项目、共享资源核心和交叉培训核心。我们将利用我们的 基因组学、蛋白质组学、肿瘤新陈代谢和免疫学方面的机构专业知识将深入研究 CRT诱导肿瘤与TME共同进化。我们的总体愿景是免疫抑制的SOC CRT与 免疫TME的变化可进一步靶向改善全身抗肿瘤免疫反应 RT.虽然我们的初步数据涉及两种免疫TME细胞类型，巨噬细胞和树突状细胞， 我们的研究设计旨在详细研究CRT对多种细胞类型的影响 我也是。因此，我们的中心可以在资助过程中调整和纳入其他细胞类型的新发现 通过试点项目和数据共享获得这笔赠款。重要的是，肿瘤细胞和TME受 肿瘤起源的组织。因此，使用这种方法来研究多种肿瘤类型以建立 CRT相关免疫抑制的常见(和肿瘤特异性)机制是什么？流星将因此而 作为一个中心，与其他研究不同肿瘤类型的罗宾中心分享这一方法。自.以来 通过我们的共享资源核心的分析方法只需要少量的活检，这将允许其他中心 把有限的样本寄给我们进行分析。此外，通过我们的行政和交叉培训中心， 我们将接待来自其他罗宾中心的教职员工和实习生，并与他们分享我们的资源、教育 将为Robin网络带来附加值的材料和方法。作为这项工作的结果，我们将 准备申请未来的NIH T32，专注于培训、传播和推进多学科 信息伙伴关系，以解决放射肿瘤学方面的关键研究差距。

Project Summary In addition to direct killing of rapidly proliferating tumor cells, radiation therapy (RT) modifies tumor immunity. RT increases the expression and release of tumor-associated antigens, induces immunogenic cell death, and releases danger signals and chemokines that recruit immune cells to the tumor microenvironment (TME). RT can also enhance tumor killing by increasing the number of tumor-infiltrating immunostimulatory cells and inducing the expression of neoantigens. However, RT also stimulates the recruitment of other myeloid derived immune cell subsets that can have tumor permissive phenotypes. The overall balance between these immune stimulatory and suppressive effects of radiation ultimately predicts whether local tumor treatment with RT generates an effective and durable systemic anti-tumor immune response. We hypothesize that RT (and in particular SOC CRT) limits the development of long-term anti-tumor immunity in resistant tumors by disproportionately increasing the number and tumor permissive phenotypes of myeloid derived cells (MDCs) in the TME. The Washington University MicroEnvironment Tumor Effects Of Radiotherapy (METEOR) Center will enable testing of this hypothesis via a dynamic Molecular Characterization Trial with closely integrated Research Projects, Shared Resource Cores, and Cross Training Core. We will leverage our institutional expertise in genomics, proteomics, tumor metabolism and immunology to take a “deep dive” into CRT induced tumor and TME co-evolution. Our overall vision is that immunosuppressive SOC CRT associated changes in the immune TME can be further targeted to improve systemic anti-tumor immune responses after RT. Although our preliminary data implicates two immune TME cell types, macrophages and dendritic cells, our research design is intended to allow for detailed study of CRT related effects on multiple cell types within the TME. As such, our Center can adapt and incorporate new findings in other cell types during the course of funding of this grant through pilot projects and data sharing. Importantly, tumor cells and the TME are influenced by the tissue of origin of the tumor. Thus, it is important to use this approach to study multiple tumor types to establish what are the common (and tumor specific) mechanisms of CRT related immunosuppression. METEOR will thus serve as a hub to share this approach with other ROBIN Centers studying different tumor types. Since the analytic approach through our Shared Resource Cores requires only small biopsies, this will allow other Centers to send limited specimens to us for analysis. Furthermore, through our Administrative and Cross Training Cores, we will host faculty and trainees from other ROBIN centers and share with them our resources, educational materials and approach which will bring added value to the ROBIN network. As a result of this work we will be well positioned to apply for a future NIH T32 focused on training, disseminating and advancing multidisciplinary informatic partnerships to address critical research gaps in radiation oncology.