Regulatory T cell modulation of reactive astrogliosis in brain metastasis

项目摘要 这项拨款提案的主要目标是研究调节性T（Treg）细胞与 脑转移性疾病背景下的反应性星形胶质细胞增生及其对脑转移过程的影响。 脑转移是癌症的最后阶段，治疗方法非常有限。不可避免地， 患有脑转移的患者在很短的时间内死于疾病。有一个强大的阻力， 脑转移的发展和星形胶质细胞的激活代表了观察到的最早的事件之一 在脑部病变形成的过程中他们的双重角色首先反对，然后支持脑转移 进展情况才刚刚开始调查。Treg细胞在发炎的脑组织中定殖和扩张， 已经显示出在中风模型中抑制反应性神经胶质增生。我们已经证明了Treg细胞消融 在早期和晚期脑转移导致脑肿瘤负荷的显着减少，并导致广泛的 反应性星形胶质细胞增生的扩大。在这项研究计划中，我们使用了体内遗传建模， 离体脑器官型切片培养、免疫组织化学、流式细胞术和单细胞RNA测序 研究Treg细胞通过以下途径促进脑转移瘤的建立和进展的假设： 调节高度异质性和可塑性反应性星形胶质细胞群。拟议研究的结果 将阐明脑转移性疾病的机制，并将提供新的机会， 未开发的治疗利基。

Project Summary The main goal of this grant proposal is to investigate the interaction between regulatory T (Treg) cells and reactive astrogliosis in the context of brain metastatic disease, and their impact on the brain metastatic process. Brain metastasis represents the final stage of cancer, for which very limited treatment is available. Inevitably, patients with brain metastasis succumb to disease in a very short time. There is a strong resistance to the initial development of brain metastasis, and the activation of astrocytes represents one of the earliest events observed during the establishment of brain lesions. Their dual role first opposing and then favoring brain metastatic progression has only started to be investigated. Treg cells colonize and expand in the inflamed brain tissue, and have been shown to inhibit reactive gliosis in a model of stroke. We have demonstrated that Treg cell ablation in early and late brain metastasis results in significant reduction of the brain tumor burden, and leads to extensive expansion of reactive astrogliosis. In this research proposal, we use a combination of in vivo genetic modeling, ex vivo brain organotypic slice cultures, immunohistochemistry, flow cytometry, and single cell RNASequencing to investigate the hypothesis that Treg cells promote the establishment and progression of brain metastasis by modulating the highly heterogenous and plastic reactive astrocyte population. Results from the proposed studies will illuminate the mechanisms of brain metastatic disease, and will provide novel opportunities based on a largely unexplored therapeutic niche.