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

项目概要 除了直接杀死快速增殖的肿瘤细胞外，放射治疗（RT）还可以改变肿瘤免疫力。 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免疫刺激细胞的数量来增强肿瘤杀伤作用 诱导新抗原的表达。然而，RT 也会刺激其他骨髓源性细胞的募集。 可以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 放射的刺激和抑制作用最终预测局部肿瘤是否接受放疗治疗 产生有效且持久的全身抗肿瘤免疫反应。我们假设 RT（并且在 特别的 SOC CRT）限制了耐药肿瘤中长期抗肿瘤免疫的发展 不成比例地增加骨髓来源细胞（MDC）的数量和肿瘤允许表型 TME。华盛顿大学放射治疗微环境肿瘤效应 (METEOR) 该中心将通过密切合作的动态分子表征试验来测试这一假设 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、肿瘤代谢和免疫学方面的机构专业知识，以“深入研究” CRT 诱导肿瘤和 TME 共同进化。我们的总体愿景是免疫抑制 SOC CRT 相关 免疫TME的变化可以进一步有针对性地改善全身抗肿瘤免疫反应 RT。尽管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 TME。因此，我们的中心可以在资助过程中适应并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 受到 肿瘤的起源组织。因此，使用这种方法研究多种肿瘤类型以确定 CRT 相关免疫抑制的常见（和肿瘤特异性）机制是什么？ METEOR 将因此 作为与其他研究不同肿瘤类型的 ROBIN 中心分享这种方法的中心。自从 通过我们的共享资源核心的分析方法只需要小活检，这将允许其他中心 将有限的样本发送给我们进行分析。此外，通过我们的管理和交叉培训核心， 我们将接待来自其他 ROBIN 中心的教师和学员，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。这项工作的结果是，我们将 非常适合申请未来的 NIH T32，重点是培训、传播和推进多学科 信息伙伴关系，以解决放射肿瘤学的关键研究差距。

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.